Actions of Analgesics on Nerve Conduction

Actions of Analgesics on Nerve Conduction: Comparison

Please note this is a comparison between Version 4 by Peter Tang and Version 3 by Eiichi Kumamoto.

Abstract

Action potential (AP) conduction in nerve fibers plays a　crucial role in transmitting nociceptive information from the periphery to cerebral cortex. It is possible that nerve AP conduction inhibition results in analgesia. Many of analgesics are well-known to suppress nerve AP conduction and voltage-gated Na⁺ and K⁺ channels involved in AP conduction. Compound action potential (CAP) recorded from a bundle of nerve fibers is a measure to know whether nerve AP conduction is affected by analgesics. This review article mentions the inhibitory effects of clinically-used analgesics, analgesic adjuvants and plant-derived analgesics on fast-conducting CAPs and voltage-gated Na⁺ and K⁺ channels. Their effects were compared in efficacy among the compounds and it was revealed that some of them have similar efficacies in suppressing CAPs. Nerve AP conduction inhibition produced by the analgesics is suggested to contribute to at least a part of their antinociceptive effects.

analgesic
antinociception
nerve conduction
sciatic nerve
compound action potential
Na+ channel
K+ channel

1. Introduction

Information of nociceptive stimuli given to the periphery is mainly transmitted through primary-afferent myelinated Aδ and unmyelinated C fibers to the spinal cord and brain stem and then to the brain by action potential (AP) conduction in nerve fibers and chemical transmission at synapses (see ^[1][2][3][4] for review). Acute nociceptive pain caused by tissue injury or damage is a physiological mechanism that serves to protect a person against injury and is usually alleviated by antipyretic analgesics including non-steroidal anti-inflammatory drugs (NSAIDs) and narcotic analgesics such as opioids. On the other hand, chronic pain, which may persist or recur for longer than three months, is a debilitating disease accompanied by spontaneous pain, etc. and is often resistant to analgesics such as NSAIDs and opioids. One of the chronic pain, neuropathic pain, occurs as a result of direct injury of the peripheral nervous system (PNS) and damage to the central nervous system (CNS), and is characterized by a hyper-excitability of neurons near injured or damaged neuronal tissues (see ^[5] for review). This type of pain is alleviated by using analgesic adjuvants such as local anesthetics, antiepileptics, antidepressants and α₂-adrenoceptor agonists (see ^{[6][7][8][9][10][11][12][13][14][15]} for review). Although analgesics and analgesic adjuvants generally depress excitatory synaptic transmission (see ^[16][17][18] for review), many of their drugs possibly suppress nerve AP conduction, in part contributing to their inhibitory effects on pain. Plants and their constituents are used as folk remedies to relieve pain as a drug with few side effects (see ^[19][20][21] for review).

AP conduction is mediated by voltage-gated Na⁺ and K⁺ channels expressed in nerve fibers. Thus, a depolarizing stimulus given to a point of nerve fiber activates Na⁺ channels located in membranes of the fiber, leading to Na⁺ entry to the cytoplasm, owing to the gradient of the electrochemical potential of Na⁺, resulting in a self-regenerative production of AP. This in turn produces an outward current (membrane depolarization) in a fiber point adjacent to the point to open other Na⁺ channels. Such an AP production subsides by a subsequent Na⁺ channel inactivation and K⁺ channel activation (see ^[22][23] for review).

AP current flowing on the surface of a nerve trunk consisting of many fibers can be measured as a compound action potential (CAP) by immersing the nerve in an isolator such as air, oil or sucrose and then by putting two electrodes on the nerve. Voltage-gated Na⁺-channel blocker tetrodotoxin (TTX)-sensitive and fast-conducting (possibly primary-afferent Aα fiber-mediated) CAPs can be easily observed in the sciatic nerve trunk isolated from frogs by exposing the nerve trunk to air (known as air-gap method). A half-peak duration of the CAP was increased by a voltage-gated delayed-rectifier K⁺-channel inhibitor tetraethylammonium with no change in its peak amplitude, indicating an involvement of K⁺ channels (see ^[24] for review). Although the frog sciatic nerve exhibits not only fast-conducting but also slow-conducting (Aδ-fiber and C-fiber mediated) CAPs, the latter CAP has much smaller peak amplitude and conduction velocity than the former CAP ^[25].

Fast-conducting CAPs recorded from the frog sciatic nerve were found to be inhibited by antinociceptive drugs in a manner dependent on their concentrations and chemical structures. Among the drugs, there are clinically-used antinociceptive drugs such as NSAIDs ^[26], many kinds of opioids including tramadol ^[27][28], many amide- and ester-type local anesthetics ^{[27][28][29][30][31][32]}, antiepileptics ^[29], antidepressants ^[33], an α₂-adrenoceptor agonist dexmedetomidine (DEX; (+)-(S)-4-[1-(2,3-dimethylphenyl)-ethyl]-1H-imidazole; ^[34]), and many kinds of antinociceptive plant-derived compounds (see ^[35] for review). This review article will describe the effects of their chemical compounds on CAPs recorded from the frog sciatic nerve and discuss a difference in nerve AP conduction inhibition among the drugs. For comparison, it will be mentioned how the antinociceptive drugs affect mammalian peripheral nerve CAPs and voltage-gated Na⁺ and K⁺ channels involved in AP production, when data are available.

Actions of Analgesics on Nerve AP Conduction

2. Actions of Analgesics on Nerve AP Conduction

2.1. NSAIDs

NSAIDs produce antinociception by various mechanisms including inhibition of the synthesis of prostaglandins from arachidonic acid by inhibiting the cyclooxygenase enzyme (^[36][37]; see ^{[38][39][40][41]} for review), activation of several K⁺ channels (^{[42][43][44][45][46]}; see ^[47][48] for review), inhibition of acid-sensitive ion channels ^[49] and transient receptor potential (TRP) channels ^[50][51], depletion of substance P ^[52], an interaction with the adrenergic nervous system ^[53] and an involvement of opioids ^[54][55] and endocannabinoids (see ^[56] for review). The idea that antinociception is produced by mechanisms other than cyclooxygenase inhibition is supported by the observation that there is a dissociation between antinociception and anti-inflammation produced by NSAIDs ^[57].

An acetic acid-based NSAID diclofenac inhibited frog sciatic nerve CAPs in a partially reversible manner with a half-maximal inhibitory concentration (IC₅₀) value of 0.94 mM in a concentration range of 0.01-1 mM. Another acetic acid-based NSAID aceclofenac, which is a carboxymethyl ester of diclofenac, also depressed CAPs in a concentration range of 0.01-1 mM with an IC₅₀ of 0.47 mM, a value smaller than that of diclofenac. Other acetic acid-based NSAIDs exhibited a similar CAP inhibition, albeit being smaller in extent than diclofenac and aceclofenac. Indomethacin at 1 mM reduced CAP peak amplitudes by 38%, and acemetacin, where the -OH group of indomethacin is substituted by -OCH₂COOH, at 0.5 mM reduced CAP peak amplitudes by 38%. Etodolac at 1 mM reduced CAP peak amplitudes by only 15%, and sulindac and felbinac at 1 mM unaffected CAP peak amplitudes ^[26].

Frog sciatic nerve CAP peak amplitudes were reduced by fenamic acid-based NSAIDs (tolfenamic acid, meclofenamic acid, mefenamic acid and flufenamic acid) having a chemical structure similar to those of diclofenac and aceclofenac in a concentration-dependent manner. Tolfenamic acid reduced CAP peak amplitudes with an IC₅₀ value of 0.29 mM in a concentration range of 0.01-0.2 mM. Meclofenamic acid, where the chloro group bound to the benzene ring of tolfenamic acid is altered in number and position, had an IC₅₀ value of 0.19 mM in a concentration range of 0.01-0.5 mM. Moreover, mefenamic acid, where the chloro group bound to the benzene ring of tolfenamic acid is replaced by methyl group, reduced CAP peak amplitudes in a concentration range of 0.01-0.2 mM (by 16% at 0.2 mM). Flufenamic acid, where one out of two methyl groups bound to the benzene ring of mefenamic acid is lacking and another one is replaced by -CF₃, exhibited an IC₅₀ of 0.22 mM, a value similar to those of tolfenamic acid and meclofenamic acid ^[26]. With respect to other types of NSAIDs, frog sciatic nerve CAPs were not affected by salicylic acid-based (aspirin; 1 mM), propionic acid-based (ketoprofen, naproxen, ibuprofen, loxoprofen and flurbiprofen; each 1 mM) and enolic acid-based NSAIDs [meloxicam (0.5 mM) and piroxicam (1 mM)] ^[26].

On the other hand, frog sciatic nerve CAPs were concentration-dependently inhibited by 2,6-dichlorodiphenylamine and N-phenylanthranilic acid, which are not NSAIDs while being similar in chemical structure to diclofenac and tolfenamic acid. Thus, 2,6-dichlorodiphenylamine lacks the -CH₂COOH group of diclofenac and N-phenylanthranilic acid lacks chloro and methyl groups bound to the benzene ring of tolfenamic acid. 2,6-Dichlorodiphenylamine activity was seen in a concentration range of 0.001-0.1 mM with the extent of 45% at 0.1 mM. N-phenylanthranilic acid activity was seen in a concentration range of 0.01-2 mM with the extent of 23% at 1 mM ^[26].

The NSAIDs-induced CAP inhibition would be mediated by a suppression of TTX-sensitive voltage-gated Na⁺ channels that are involved in producing frog CAPs. Consistent with this idea, diclofenac reduced TTX-sensitive Na⁺-channel current amplitudes in rat dorsal root ganglion (DRG) ^[58] and mouse trigeminal ganglion neurons ^[59]. A similar Na⁺-channel inhibition produced by diclofenac has been reported in rat myoblasts ^[60] and ventricular cardiomyocytes ^[61]. Like diclofenac, flufenamic acid reduced Na⁺-channel current amplitudes in rat hippocampal CA1 neurons ^[62][63][64]. Although IC₅₀ value (0.22 mM) for flufenamic acid to suppress frog sciatic nerve CAPs was close to that (0.189 mM) of Na⁺ channel inhibition in rat hippocampal CA1 neurons ^[64], IC₅₀ value (0.94 mM) for diclofenac-induced CAP inhibition was much larger than those (0.014 and 0.00851 mM in rat DRG neurons and myoblasts, respectively) for Na⁺ channel inhibition ^[58][60]. Rank order for CAP inhibition by NSAIDs at 0.5 mM was flufenamic acid > diclofenac > indomethacin >> aspirin = naproxen = ibuprofen ^[26]. This order was partly similar to those for Na⁺ channel suppression in rat DRG neurons (diclofenac > flufenamic acid > indomethacin > aspirin; ^[58]) and also in rat cardiomyocytes (diclofenac > naproxen ≥ ibuprofen; ^[61]). Diclofenac at 0.3 mM reduced by about 20% TTX-resistant Na⁺-channel current amplitudes in rat trigeminal ganglion neurons ^[65]. TTX-resistant Nav1.8 channel current amplitudes were reduced by flufenamic acid and tolfenamic acid at 0.1 mM with the extents of about 30 and 30%, respectively ^[66]. TTX-sensitive Nav1.7 channel currents were more sensitive to flufenamic acid and tolfenamic acid (extent at 0.1 mM: about 60 and 70%, respectively) than TTX-resistant Nav1.8 ones ^[66]. Alternatively, NSAIDs inhibited the extent of chemical irritation-induced activity increase of cat corneal sensory nerve fibers; this inhibition was different in extent among different types of NSAIDs ^[59][67]. NSAIDs-induced Na⁺-channel inhibition appeared to be distinct in magnitude among preparations. Concentrations needed for NSAIDs to significantly inhibit frog sciatic nerve CAPs were generally higher than those necessary for Na⁺ channel inhibition. This result may be due to various factors such as the involvement of not only Na⁺ channels but also K⁺ channels in CAP peak amplitudes. As far as I know, it has not been reported how the aceclofenac, indomethacin, etodolac, acemetacin, meclofenamic acid and mefenamic acid affect voltage-gated Na⁺ channels. Table 1 summarizes the actions of NSAIDs on frog sciatic nerve fast-conducting CAPs together with their IC₅₀values (see also ^[68]).

More effective NSAIDs in inhibiting frog sciatic nerve CAPs have two benzene rings that bind a hydrophilic substituent group, both of which rings are linked by -NH- (see Figs. 1Aa, 1Ba, 3Aa, 3Ba, 3Da in ^[26] for the chemical structures of diclofenac, aceclofenac, tolfenamic acid, meclofenamic acid and flufenamic acid). Such a chemical structure is seen in local anesthetics (see Section 3.1) but not in the other NSAIDs ^[26]. Mefenamic acid, where one of the two benzene rings has a hydrophobic substituent group (see Fig. 3Ca in ^[26]), seemed to be less effective in CAP inhibition, albeit not tested at a higher concentration owing to a less solubility of this drug (see above). CAPs were effectively inhibited by 2,6-dichlorodiphenylamine and N-phenylanthranilic acid, which are similar in chemical structure to NSAIDs having two benzene rings (see Figs. 4Aa and 4Ba in ^[26]), albeit they are not NSAIDs. CAPs were also suppressed by the endocrine disruptor bisphenol A having two benzene rings that bind a hydrophilic group such as -OH ^[31].

There is much evidence showing that the other actions of NSAIDs are dependent on their chemical structures. For example, an involvement of NO-cyclic GMP-K⁺ channels in NSAIDs-induced antinociception depended on their chemical structures ^[45][69]. Nonselective cation channels in the rat exocrine pancreas were inhibited by flufenamic acid and mefenamic acid but not indomethacin, aspirin and ibuprofen ^[70]. There was a difference between diclofenac and aceclofenac in inhibiting TRP melastatin-3 channels ^[51]. Although TRP ankyrin-1 (TRPA1) channels were depressed or activated by NSAIDs, such an activity also differed in extent among NSAIDs ^[71]. Moreover, a difference was seen among NSAIDs in the activities of electron transport system or mitochondrial oxidative phosphorylation that may produce NSAIDs’ adverse side effects ^[72].

As stated above, the concentrations for NSAIDs to inhibit frog sciatic nerve CAPs are generally much higher than those for voltage-gated Na⁺-channel inhibition. Such high concentrations will be possible when NSAIDs are used in the direct vicinity of nerve fibers. At least a part of analgesia produced by NSAIDs used as a dermatological drug may be explained by a nerve AP conduction inhibition through suppressed voltage-gated Na⁺ channels ^[73].

2.2. Opioids

Opioids suppress glutamatergic excitatory transmission by activating opioid receptors expressed in the CNS including the central terminals of primary-afferent fibers, leading to antinociception (^[74][75][76]; see ^[77][78] for review). Opioid receptors are located in not only central but also peripheral terminals of primary-afferent neurons; peripheral terminal opioid receptors are known to be involved in antinociception (^{[79][80][81][82][83]}; see ^[84] for review). Opioids also have a local anesthetic effect in the PNS. Although the perineural administration of an opioid morphine is reported to have no effect on CAPs in the superficial radial nerve in decerebrated cats ^[85], AP conduction in peripheral nerve fibers is generally inhibited by opioids. For example, opioids such as fentanyl and sufentanil reduced the peak amplitudes of CAPs recorded from peripheral nerve fibers ^[86] and depressed peripheral nerve AP conduction ^[87]. A morphine-induced CAP inhibition in mammalian peripheral nerve fibers was sensitive to a nonspecific opioid-receptor antagonist naloxone, indicating an involvement of opioid receptors ^[88]. Consistent with this observation, binding and immunohistochemical studies have demonstrated the localization of opioid receptors in mammalian peripheral nerve fibers ^[89][90][91].

2.2.1. Tramadol

Tramadol [(1RS; 2RS)-2-[(dimethylamino) methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride] is an orally-active and clinically-used opioid in the CNS ^[92]. In animals and humans, tramadol is metabolized to various compounds including mono-O-desmethyl-tramadol (M1) through N- and O-demethylation ^[93]; M1 is a therapeutically active drug to alleviate pain ^[92]. Among cellular mechanisms for the tramadol’s antinociceptive effect, there is μ-opioid receptor activation ^[94][95]. This idea is supported by the highest affinity of M1 among the metabolites of tramadol for cloned μ-opioid receptors. M1 inhibited glutamatergic excitatory transmission in spinal lamina II neurons which play a pivotal role in regulating nociceptive transmission to the spinal dorsal horn from the periphery, resulting in reducing the excitability of the neurons ^[96][97][98]. In addition to such a central activity, tramadol has a local anesthetic effect following its intradermal injection in patients (^{[99][100][101]}; see ^[102] for review). This result was consistent with in vivo studies showing an inhibition of a spinal somatosensory evoked potential, produced by a direct application of tramadol to the rat sciatic nerve ^[103]. Tramadol used as an adjuvant to local anesthetics has been reported to prolong the duration of sensory block and analgesia ^[104].

CAPs recorded from the frog sciatic nerve were reduced in peak amplitude by tramadol in a concentration-dependent manner in a range of 0.2 to 5 mM ^[27]. A similar tramadol’s CAP inhibitory action has been demonstrated by other investigators in the frog ^[105] and rat sciatic nerve ^[106][107]. According to ourthe analysis based on the Hill equation, IC₅₀ value for tramadol to reduce frog sciatic nerve CAP amplitude was 2.3 mM, a value being smaller by about three-fold than that (6.6 mM) reported by Mert et al. ^[105] for the frog sciatic nerve. Tramadol also suppressed rat sciatic nerve CAPs (37% peak amplitude reduction at 4 mM; ^[106]) with an extent less than that obtained by Katsuki et al. ^[27] for frog sciatic nerve CAPs. The tramadol action in the frog sciatic nerve was unaffected by the pretreatment of the nerve with naloxone (0.01 mM) and a μ-opioid receptor agonist (D-Ala², N-Me-Phe⁴, Gly⁵-ol)enkephalin (DAMGO; 1 μM) had no effect on frog sciatic nerve CAPs ^[27]. As different from tramadol, M1 inhibited CAPs by much smaller extents (see below), although M1 has a higher affinity for μ-opioid receptors than tramadol, the chemical structure of which is similar to that of M1 ^[108]. These results indicate that opioid receptors are not involved in tramadol-induced CAP inhibition ^[27]. This idea is consistent with the observation that a spinal somatosensory evoked potential inhibition produced by tramadol in rat sciatic nerves in vivo was unaffected by naloxone ^[103]. Jaffe and Rowe ^[87] also have reported a naloxone-resistant nerve AP conduction inhibition produced by opioids.

Although tramadol inhibits noradrenaline (NA) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at concentrations enough to activate μ-opioid receptors ^[109][110], a combination of NA and 5-HT reuptake inhibitors (desipramine and fluoxetine, respectively; each 10 μM; see Section 3.3) unaffected frog sciatic nerve CAPs, indicating that CAP inhibition was not mediated by NA and 5-HT reuptake inhibition ^[27].

It is possible that the tramadol-induced CAP inhibition is mediated by an inhibition of voltage-gated Na⁺ and K⁺ channels involved in AP production. Tramadol concentration-dependently reduced TTX-sensitive Na⁺ channel current amplitude with an IC₅₀ value of 0.194 mM in DRG neuroblastoma hybridoma cell line ND7/23 cells ^[111] and also with an IC₅₀ value of 0.103 mM in HEK293 cells expressing rat TTX-sensitive Nav1.2 channels ^[112]. These values were smaller than that (2.3 mM) of IC₅₀ for frog sciatic nerve CAP amplitude reduction ^[27]. Tramadol also decreased the current amplitude of delayed rectifier K⁺-channels (Kv3.1a type) expressed in NG 108-15 cells with an IC₅₀ of 0.025 mM; this value was much less than 2.3 mM ^[113]. Such IC₅₀ values of tramadol for CAP, Na⁺ and K⁺ channel inhibition were higher than its clinically relevant concentration of about 2 μM in serum ^[98][114].

On the other hand, frog sciatic nerve CAPs were unaffected by M1 (1-2 mM), as different from tramadol. Moreover, in the frog sciatic nerve exhibiting CAP inhibition by tramadol (1 mM; ^[27]), M1 at 5 mM reduced CAP peak amplitudes by only 9%. Consistent with such smaller effects of M1, M1 (1 mM) did not block APs conducting on rat primary-afferent fibers when its effect on dorsal root-evoked excitatory postsynaptic currents was investigated by applying the patch-clamp technique to lamina II neurons in spinal cord slices ^[97]. Interestingly, tramadol has -OCH₃ while M1 has -OH bound to the benzene ring, and thus the methyl group is present in tramadol but not M1 (see Fig. 5a in ^[27]). In conclusion, the distinction in CAP inhibition between tramadol and M1 could be explained by the difference in chemical structure.

2.2.2. Morphine, Codeine and Ethylmorphine

In order to know whether the structure-activity relationship between tramadol and M1 is applied to other opioids, it was examined how frog sciatic nerve CAPs are affected by morphine, codeine (which has -OCH₃ in place of -OH in morphine) and ethylmorphine (where -OH of morphine is replaced by -OCH₂CH₃; see Fig. 7A in ^[28] for their chemical structures). CAP peak amplitude was reduced by morphine in a concentration-dependent manner with an extent of 15% at 5 mM. Codeine at 5 mM reduced CAP peak amplitude by 30%. Ethylmorphine inhibited CAPs more effectively than morphine and coceine with an IC₅₀ value of 4.6 mM (inhibition at 5 mM: 61%). The activities of morphine, codeine and ethylmorphine were resistant to naloxone (0.01 mM). Naloxone at 1 mM by itself reduced by 9% CAP peak amplitudes, while unaffecting morphine activity ^[28]. These results indicate that the CAP inhibitions produced by opioids were not mediated by opioid receptors, an observation similar to those of mammalian peripheral nerves ^{[86][87][115]}. On the contrary, Hunter and Frank ^[116] have reported a naloxone-sensitive CAP inhibition in the frog sciatic nerve. A sequence of the CAP peak amplitude reduction produced by opioids was ethylmorphine > codeine > morphine, indicating that CAP inhibition increases in extent with an increase in the number of -CH₂. This result was consistent with the relationship between tramadol and M1, as mentioned above. It is of interest to note that morphine, codeine and ethylmorphine are quite distinct in chemical structure from tramadol and M1 (see ^[117] for review). Since the increase in -CH₂ number enhances lipophilicity of opioids, it is suggested that lipophilic opioid-channel interaction plays a crucial role in inhibiting nerve AP conduction, as shown for local anesthetics ^[118][119]. Consistent with this idea, a potency of rat sciatic nerve CAP inhibition was in the order of isopropylcocaine > cocaethylene > cocaine ^[120]. Interestingly, the sequence of an affinity of opioids for μ-opioid receptors is morphine > codeine > ethylmorphine ^[121]; this order is reversed to that of CAP inhibition. This result supports the idea that frog sciatic nerve CAP inhibition produced by opioids is not due to opioid receptor activation.

CAP inhibition similar to that in the frog sciatic nerve has been reported in the mammalian peripheral nerve, although its extent is different among preparations. Frog sciatic nerve CAP peak amplitude reduction (about 30%) produced by codeine (5 mM) was much smaller than that (about 70%) in the rat phrenic nerve, while there was not so a large difference in morphine (5 mM) action (about 10%) between the two preparations. Morphine sensitivity was less in the frog sciatic nerve than rabbit and guinea-pig vagus nerves whose CAP peak amplitudes were reduced by 20-32% at 0.5 mM ^[88]. Intracellularly-recorded APs in rat DRG neurons having Aα/β myelinated primary-afferent fibers were also inhibited by opioids with a sequence of ethylmorphine > codeine ≥ morphine (IC₅₀ = 0.70, 2.5 and 2.9 mM, respectively) in AP peak amplitude reduction. These AP inhibitions were also resistant to naloxone (0.01 mM) ^[122].

AP conduction in peripheral nerve fibers is inhibited by many drugs including narcotics, antiepileptics, local anesthetics, alcohols and barbiturates, suggesting that the drugs may interact with membrane bilayers in a nonspecific manner ^[123]. However, the above-mentioned chemical structure-specific CAP inhibition produced by opioids indicates that opioids act on membrane proteins such as voltage-gated Na⁺ and K⁺ channels (see ^[124] for review). In support of this idea, morphine inhibited peak Na⁺ channel currents and steady-state K⁺ channel currents recorded from frog sciatic nerve single myelinated nerve fibers, resulting in the prolongation of APs ^[125]. The intracellular application of morphine resulted in the reduction of voltage-gated Na⁺ and K⁺ channel current amplitudes in squid giant axons ^[126]. Bath application of morphine led to the reduction of TTX-sensitive Na⁺ channel current amplitude in DRG neuroblastoma hybridoma cell line ND7/23 cells with an IC₅₀ value of 0.378 mM ^[111], whereas TTX-sensitive Nav1.2 channels located in HEK293 cells were unaffected by morphine at 1 mM ^[112]. Supporting the idea about ion channel inhibition, an opioid meperidine, which was used for AP conduction blockade and thus analgesia, depressed Na⁺-channels in a manner similar to that of lidocaine ^[127]. Table 1 summarizes the inhibitory actions of opioids on frog sciatic nerve fast-conducting CAPs together with their IC₅₀values (see also ^[68]).

In clinical practice, many of pain treatments by using opioids are due to systemic administration of centrally-penetrating opioids, leading to their actions in the PNS and CNS, both of which contribute to analgesia (see ^[128] for review). Administration of opioids into the nerve sheath also could alleviate pain (for instance, see ^[129]). It is likely that centrally-administrated opioids act on not only the CNS but also the PNS, because opioids are transported to the periphery from brain by P-glycoprotein ^[130]. Supporting this idea, subcutaneous administration of blood brain barrier-impermeable N-methyl-morphine produced antinociception in an acetic acid-writhing model in mice ^[79]. A subcutaneously-administrated opioid loperamide, which is impermeable into the brain, had an antinociceptive effect in the formalin test in rats ^[81]. Thus, nerve AP conduction inhibition produced by opioids might contribute to local analgesia following the peripheral perineural administration of opioids (for instance, see ^[131]) that may lead to a direct action of opioids at high doses on peripheral nerves. Peripherally-applied codeine might have a similar effect to that of morphine, because codeine is metabolized to morphine via O-demethylation in humans and animals (^[132][133]; see ^[128] for review).

Actions of Analgesic Adjuvants on Nerve AP Conduction

3. Actions of Analgesic Adjuvants on Nerve AP Conduction

3.1. Local Anesthetics

Local anesthetics inhibit both voltage-gated Na⁺ and K⁺ channels (^[118]; see ^{[124][134][135]} for review). Owing to this inhibition, local anesthetics have been used to alleviate neuropathic pain in the hope of suppressing nerve AP conduction in animals ^[136][137] and humans ^{[138][139][140][141]}, although it is possible that other effects such as the modulation of neurotransmitter receptors, toll-like receptors and TRP channels are also involved in analgesia (see ^[134] for review]. Various types of local anesthetics are reported to activate TRPA1 channels in the central terminals of primary-afferent neurons in lamina II of the rat spinal dorsal horn ^[142][143], and also TRPA1 and TRP vanilloid-1 (TRPV1) channels in rodent DRG neurons ^[144][145].

3.1.1. Amide-type Local Anesthetics

Frog sciatic nerve CAPs were reversibly reduced in peak amplitude by an amide-type local anesthetic lidocaine, which blocks nerve AP conduction ^{[105][106][107][135]}, in a concentration range of 0.1 to 2 mM with an IC₅₀ value of 0.74 mM ^[28]. This IC₅₀ value was somewhat larger than that (0.204 mM) for voltage-gated Na⁺-channel current amplitude reduction while being smaller than that (1.118 mM) for voltage-gated K⁺-channel current amplitude reduction in Xenopus laevis sciatic nerve fibers ^[119]. Rat TTX-resistant Na⁺ channel current amplitude was reduced by lidocaine with an IC₅₀ of 0.073 mM ^[146], a value 10-fold lower than that for frog sciatic nerve CAP amplitude reduction. At a least of antinociception produced by systemically-applied lidocaine in humans ^[147] may be attributed to its inhibitory effect on nerve AP conduction.

A similar reversible CAP amplitude reduction was produced by another amide-type local anesthetic ropivacaine, which exhibits a longer duration of action in terms of nerve AP conduction block than lidocaine does (^[148]; see ^[149]] for review); this reduction was concentration-dependent in a range of 0.01-1 mM with an IC₅₀ value of 0.34 mM ^[27]. The frog sciatic nerve ropivacaine-induced CAP amplitude reduction was almost comparable in extent to that (about 30% at 0.2 mM) in rabbit vagus nerve A fibers ^[150]. Frog sciatic nerve IC₅₀ values for lidocaine and ropivacaine (0.74 and 0.34 mM, respectively) were not so distinct from those (0.28 mM for both lidocaine and ropivacaine) for fast-conducting CAP amplitude reduction in the rat sciatic nerve ^[151]. Moreover, an amide-type local anesthetic prilocaine also reversibly reduced frog sciatic nerve CAP peak amplitudes in a concentration-dependent manner in a range of 0.01-5 mM with an IC₅₀ value of 1.8 mM ^[31].

As amide-type local anesthetics, there are levobupivacaine and its racemic bupivacaine, the former of which has a lower risk of cardiovascular and CNS toxicity than the latter (^[152]; see ^[153] for review). Frog sciatic nerve CAP peak amplitudes were reversibly reduced by levobupivacaine in a concentration-dependent manner in a range of 0.05-1 mM with an IC₅₀ value of 0.23 mM ^[29]. This IC₅₀value was close to that (0.22 mM) reported previously for a tonic levobupivacaine-induced inhibition of frog sciatic nerve CAPs ^[152] and to that (0.264 mM) for a tonic levobupivacaine-induced suppression of voltage-gated Na⁺-channel currents recorded at -100 mV in GH-3 neuroendocrine cells ^[154]. As shown previously ^[152], the levobupivacaine-induced CAP amplitude reduction in the frog sciatic nerve was smaller than that of bupivacaine (their extents at 0.5 mM: 45 and 76%, respectively; ^[29]). This frog sciatic nerve bupivacaine activity was smaller than that (IC₅₀ = 0.027 mM) for Na⁺-channels in Xenopus laevis sciatic nerve fibers ^[119], that (IC₅₀ = 0.178 mM) for TTX-sensitive Na⁺ channels in DRG neuroblastoma hybridoma cell line ND7/23 cells ^[155] and that (IC₅₀ = 0.190 mM) for Na⁺ channels in rat clonal pituitary GH₃ cells ^[156]. Voltage-gated K⁺ channels in Xenopus laevis sciatic nerve fibers were also inhibited by bupivacaine with a sensitivity (IC₅₀ = 0.092 mM) less than that for Na⁺ channels ^[119].

3.1.2. Ester-type Local Anesthetics

As a classic ester-type local anesthetic, there is a compound derived from the coca plant Erythroxylon coca, cocaine, which is well-known to inhibit nerve AP conduction (^{[115][157][158]}; see ^[159] for review). Frog sciatic nerve CAP peak amplitude was reversibly reduced by cocaine in a concentration-dependent manner in a range of 0.01-2 mM with an IC₅₀ of 0.80 mM ^[28], a value similar to that (0.74 mM) of lidocaine in the frog sciatic nerve ^[27]. The cocaine’s IC₅₀ value was about 4-fold larger than that (about 0.2 mM) in the rat phrenic nerve ^[115]. Although cocaine (40 μM) reduced mouse phrenic nerve CAP peak amplitudes by 26% ^[158], such a reduction in the frog sciatic nerve was produced at a concentration of about 300 μM ^[28]. There was an almost similar CAP amplitude reduction by cocaine in the frog and rat sciatic nerve (frog: 30% at 0.5 mM; rat: 40% at 0.375 mM; see ^[120]). There is much evidence for an inhibition by cocaine of voltage-gated Na⁺ channels (for example, see ^{[120][160][161]}); a cocaine (0.05 mM)-induced tonic (TTX-resistant) Nav1.5 channel current amplitude reduction is about 70% ^[161]. Cocaine and lidocaine suppressed voltage-gated Na⁺ channels in a competitive manner ^[162]. Cocaine also inhibited delayed rectifier K⁺ channels in central snail neurons ^[163].

Another ester-type local anesthetic procaine ^[164] also reversibly reduced frog sciatic nerve CAP peak amplitudes in a concentration-dependent manner in a range of 0.1-5 mM with an IC₅₀ value of 2.2 mM ^[32]. This IC₅₀value was close to those (2-5 mM) obtained by other researchers ^[165][166] in the same preparation and also to that (about 1 mM) reported in the rat sciatic nerve [165]. Moreover, a ratio (2.2 mM/0.74 mM) of the procaine’s IC₅₀ value to that of lidocaine ^[27] in reducing frog sciatic nerve CAP amplitudes was comparable to a ratio (0.53%/0.14%) of procaine concentration, necessary to block motor nerve AP conduction by 50%, to lidocaine’s one in rats ^[167]. On the other hand, procaine activity in the frog sciatic nerve was 37-fold smaller than that (IC₅₀ = 0.060 mM) in reducing voltage-gated Na⁺-channel current amplitude in Xenopus laevis sciatic nerve fibers ^[119]. Procaine also suppressed voltage-gated K⁺ channels in this preparation with an IC₅₀ value (6.303 mM) larger than that for Na⁺ channels ^[119].

There is an ester-type local anesthetic benzocaine (ethyl 4-aminobenzoate) that is used for not only topical anesthesia in clinical medicine (see ^[168] for review) but also amphibian anesthesia (^[169]; see ^[170][171] for review). Frog sciatic nerve CAP peak amplitudes were reversibly reduced by benzocaine in a concentration-dependent manner in a range of 0.01-2 mM with an IC₅₀ value of 0.80 mM (73% reduction at 1 mM; ^[30]). The rat sciatic nerve exhibited a similar benzocaine-induced CAP inhibition (37% inhibition at 1.3 mM; ^[106]). The benzocaine activity was similar to those of cocaine and lidocaine.

Another ester-type local anesthetic tetracaine also reduced frog CAP peak amplitudes in a reversible and concentration-dependent manner with an IC₅₀ value of 0.014 mM ^[34]. This IC₅₀ value is not so different from that (0.0063 mM) of frog sciatic nerve fibers, as reported by Starke at al. ^[172], and also from that (0.009 mM) obtained for rabbit A nerve fibers ^[173]. On the other hand, the tetracaine activity in the frog sciatic nerve was 19-fold smaller than that (IC₅₀ = 0.0007 mM) for voltage-gated Na⁺-channel current amplitude reduction in Xenopus laevis sciatic nerve fibers ^[119]. Voltage-gated K⁺-channel current amplitudes in this preparation were also reduced by tetracaine with an IC₅₀ value (0.946 mM) much larger than that for Na⁺ channels ^[119]. Tetracaine had much more effectiveness than procaine and also lidocaine and bupivacaine in both frog CAP and Xenopus laevis Na⁺-channel current inhibition.

Frog sciatic nerve CAP peak amplitudes were also reduced by a non-amide- and non-ester-type local anesthetic pramoxine. This inhibitory action of pramoxine was concentration-dependent in a range of 0.001-1 mM with an IC₅₀ value of 0.21 mM and subsided with a slow time course after its washout ^[31]. Table 1 summarizes the inhibitory actions of local anesthetics on frog sciatic nerve fast-conducting CAPs together with their IC₅₀values (see also ^[68]).

3.2. Antiepileptics

Antiepileptics have various actions such as glutamate-receptor inhibition, GABA_A-receptor activation, voltage-gated Na⁺- and Ca²⁺-channel inhibition (see ^[13][174] for review). Antiepileptics are well-known to inhibit neuropathic pain (for example, see ^[175]). As indicated by the action on Na⁺ channels, it is possible that the neuropathic pain alleviation is due to nerve AP conduction inhibition.

Frog sciatic nerve CAP peak amplitudes were reduced by a phenyltriazine derivative (lamotrigine; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) that suppressed voltage-gated Na⁺ channels ^[176] and also attenuated central post-stroke pain and painful diabetic poly-neuropathy ^[7]. This sciatic nerve lamotrigine activity was partially reversible and concentration-dependent in a range of 0.02-0.5 mM with an IC₅₀ value of 0.44 mM ^[29]. This value was similar to IC₅₀ value (0.641 mM at -90 mV) for lamotrigine to inhibit TTX-sensitive human brain type IIA Na⁺ channels expressed in Chinese hamster ovary cells ^[176]. A similar CAP amplitude reduction was seen by an iminostilbene derivative carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide; ^[29]), which is distinct in chemical structure from lamotrigine while inhibiting voltage-gated Na⁺ channels ^[177]. Carbamazepine is reportedly effective in attenuating trigeminal neuralgia (see ^[178][179] for review). As distinct from lamotrigine’s one, the carbamazepine-induced CAP inhibition in the frog sciatic nerve was completely reversible. This carbamazepine activity was concentration-dependent in a range of 0.05-1 mM with an IC₅₀ value of 0.50 mM ^[29]. Carbamazepine and lamotrigine reduced Na⁺-channel current amplitudes in N4TG1 mouse neuroblastoma cells with IC₅₀ values similar to each other ^[180], an observation being consistent with the fact that the two antiepileptics had comparable IC₅₀ values in reducing frog sciatic nerve CAP amplitudes.

Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide; ^[181]), where there is a keto substitution at the 10,11 position of the dibenzazepine nucleus of carbamazepine, reduced frog sciatic nerve CAP peak amplitudes with an efficacy less than that of carbamazepine ^[29]. Oxcarbazepine is known to be effective in attenuating painful diabetic neuropathy ^[7] and trigeminal neuralgia ^[178]. Oxcarbazepine activity was partially reversible and concentration-dependent in a range of 0.02-0.7 mM. CAP amplitude reduction (40%) by oxcarbazepine (0.7 mM) was somewhat smaller in extent than that (57%) of carbamazepine (0.7 mM). Each of lamotrigine, carbamazepine and oxcarbazepine at 0.5 mM increased a threshold to evoke frog sciatic nerve CAPs ^[29]. Consistent with this observation, their antiepileptics reduced voltage-gated Na⁺-channel current amplitudes with a shift of their steady-state inactivation to a more negative membrane potential ^{[180][182][183]}. Frog sciatic nerve CAP amplitude reduction produced by oxcarbazepine at 0.5 mM (20%; ^[29]) was much smaller in extent than that for TTX-sensitive Na⁺-channel current inhibition in differentiated NG108-15 neuronal cells (IC₅₀ = 3.1 μM; ^[182]). Consistent with the observation that oxcarbazepine exhibited a smaller frog sciatic nerve CAP inhibition than carbamazepine, oxcarbazepine was less effective than carbamazepine in attenuating seizures produced by maximal electroshock in rats ^[181].

Another antiepileptic phenytoin (hydantoin derivative, 5,5-diphenylhydantoin; which suppresses voltage-gated Na⁺ channels ^[184] and attenuates paroxysm in trigeminal neuralgia ^[179]) inhibited frog sciatic nerve CAPs with a small extent in a concentration-dependent manner in a range of 0.01-0.1 mM; this extent was only 15% at 0.1 mM ^[29]. The frog sciatic nerve phenytoin activity was less than those of rat cortical and human type IIA Na⁺ channels (60-90% amplitude reduction by phenytoin at 0.1 mM at -60 mV) ^[176][184]. As distinct from frog sciatic nerve CAPs, voltage-gated Na⁺ channel current amplitudes were reduced by phenytoin with an IC₅₀ value similar to lamotrigine in N4TG1 mouse neuroblastoma cells ^[182]; phenytoin, lamotrigine and carbamazepine reportedly bound to a common site of Na⁺ channels in rat hippocampal CA1 neurons ^[183]. A sensitivity of voltage-gated Na⁺ channels to phenytoin appeared to be distinct in extent among distinct types of the channel. Supporting this idea, phenytoin activities were distinct in magnitude among human Nav1.1, Nav1.2, Nav1.3 and Nav1.4 α-subunits (all of which are TTX-sensitive) expressed in HEK293 cells ^[185]. Moreover, there was a difference in the properties and accessibilities of Na⁺ channels between frog and rat myelinated nerves ^[186].

Antiepileptics having an ability to suppress CAPs are similar in chemical structure to NSAIDs in that lamotrigine, carbamazepine and oxcarbazepine have two unsaturated six-membered rings (see Figs. 1a, 2aA and 2bA in ^[29] for the chemical structures of the three antiepileptics). Carbamazepine and diclofenac appear to have a common or closely-related binding site because of an occlusion of their effects on voltage-gated Na⁺ channels ^[63].

On the other hand, frog sciatic nerve CAPs were not affected by other antiepileptics, gabapentin (1-(aminomethyl)cyclohexaneacetic acid; which is related to GABA in chemical structure and attenuates post-herpetic neuralgia ^[179]]), topiramate (2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate; which alleviates various neuropathic pains such as intercostal neuralgia and trigeminal neuralgia ^[13]) and sodium valproate (2-propylpentanoic acid sodium salt; which relieves diabetic neuropathic pain ^[13]), at a high concentration such as 10 mM ^[29]. The less effectiveness of gabapentin and sodium valproate in the frog sciatic nerve was similar to that for human type IIA Na⁺ channels ^[176]. The human Na⁺ channels were hardly affected by gabapentin at concentrations of less than 3 mM ^[176]. Gabapentin’s antinociceptive action would be due to its binding to the　α₂δ-1　subunit of voltage-gated Ca²⁺ channels, resulting in inhibited Ca²⁺ entry in nerve terminals which in turn attenuates the release of neurotransmitters from there (see ^[187] for review); gabapentin also may interrupt an interaction between N-methyl-D-aspartate (NMDA)-receptor (a subtype of glutamate receptors) channels and the α₂δ-1　subunit of voltage-gated Ca²⁺ channels in postsynaptic neurons ^[188]. As different from the frog sciatic nerve, topiramate inhibited TTX-sensitive Na⁺-channels with an IC₅₀ value of 0.0489 mM in rat cerebellar granule cells ^[189]. Such a distinction would be possibly attributed to a distinction in topiramate sensitivity among different types or phosphorylation states of Na⁺ channels ^[190]. Antinociceptive actions of sodium valproate and topiramate have been attributed to other mechanisms including GABA_A-receptor response increase (see ^[191][192] for review). Glutamate-receptor inhibition also would possibly contribute to the antinociceptions produced by topiramate and lamotrigine, because topiramate depresses GluK1 (GluR5) kainate receptors (a subtype of glutamate receptors) in rat basolateral amygdala neurons ^[193] and lamotrigine suppresses　α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors (another subtype of glutamate receptors) in rat dentate gyrus granule cells ^[194]. Table 1 summarizes the actions of antiepileptics on frog sciatic nerve fast-conducting CAPs together with their IC₅₀values (see also ^[68]).

Antiepileptics having an ability to suppress frog sciatic nerve CAPs appeared to have antinociceptive actions in a persistent pain model. Intraperitoneal application of lamotrigine, carbamazepine and oxcarbazepine produced analgesic effects in the second phase of the formalin test (that reflects inflammation occurring 15-20 min after formalin injection) whereas phenytoin, topiramate and sodium valproate did not so in rats ^[195][196].　　The antinociceptive effects of antiepileptics appeared to be partly related to nerve AP conduction inhibition produced by them. The plasma concentrations of lamotrigine and carbamazepine used to clinically treat epilepsy are, respectively, < 12 μM and 20-50 μM ^[197][198], values smaller than those of IC₅₀ for frog sciatic nerve CAP inhibition.

3.3. Antidepressants

Antidepressants are thought to alleviate pain by activating the 5-HT- and NA-containing descending antinociceptive pathway to the spinal dorsal horn from brainstem through a suppression of their neurotransmitters’ reuptake ^[199][200], involvement of α adrenoceptors, H₁-histamine, 5-HT, opioid and muscarinic acetylcholine receptors (^{[11][201][202][203][204]}; see ^[205][206] for review) and the inhibition of voltage-gated Ca²⁺ ^[207][208], NMDA-receptor ^{[209][210][211][212]} and P2X₄-receptor channels (a subtype of ionotropic P2X receptors; ^[213]), all of which are related to synaptic transmission. Moreover, an inhibition of neuroimmune mechanisms accompanying nerve injury may be involved in pain alleviation produced by antidepressants ^[214].

A 5-HT and NA reuptake inhibitor (SNRI) duloxetine (^{[215][216][217]}; see ^[218] for review) inhibited frog sciatic nerve CAPs in a partially reversible manner. Duloxetine activity was concentration-dependent in a range of 0.001-2 mM with an IC₅₀ value of 0.23 mM ^[33]. A similar CAP inhibition was produced by a selective 5-HT reuptake inhibitor (SSRI) fluoxetine (^[201][202]; see ^[206][219] for review). Fluoxetine-induced CAP peak amplitude reduction was partially reversible, concentration-dependent in a range of 0.05-5 mM and had an IC₅₀ of 1.5 mM, a value larger than that of duloxetine ^[33].

Typical tricyclic antidepressants (amitriptyline and desipramine, which are tertiary and secondary amines, respectively; ^{[200][203][220][221]}) also inhibited frog sciatic nerve CAPs. Amitriptyline reduced CAP peak amplitudes in a concentration range of 0.001-1 mM with an IC₅₀ value of 0.26 mM, and desipramine did so in a concentration range of 0.1-5 mM with an IC₅₀ value of 1.6 mM ^[33]. Thus, amitriptyline was six-fold more effective in CAP inhibition than desipramine. Consistent with this result, amitriptyline produced an AP conduction blockade in the rat sciatic nerve ^[156]. Like tricyclic antidepressants, a tetracyclic one maprotiline ^[220] also inhibited frog sciatic nerve CAPs in a partially reversible manner. Maprotiline activity was concentration-dependent in a range of 0.2-5 mM with an IC₅₀ value of 0.95 mM ^[33]. Trazodone, 5-HT₂-receptor antagonist and reuptake inhibitor (SARI), is a non-SNRI, -SSRI, -tricyclic and -tetracyclic antidepressant (^{[222][223][224][225]}; see ^[226] for review). Trazodone reduced frog sciatic nerve CAP peak amplitudes at concentrations ranging from 0.2 to 2 mM, a maximally dissolved concentration, in a partially reversible manner. The extent of trazodone (1 mM)-induced CAP peak amplitude reduction was about 50% ^[33].

The antidepressants-induced CAP inhibition would be due to an attenuation of TTX-sensitive voltage-gated Na⁺ channels which are involved in the production of frog sciatic nerve CAPs. Consistent with this idea, voltage-gated Na⁺ channels were inhibited by duloxetine ^[227][228], fluoxetine ^[229], amitriptyline ^{[227][229][230][231][232][233][234][235]}, desipramine and maprotiline ^[236]. TTX-sensitive voltage-gated Na⁺ channels in bovine adrenal chromaffin cells were suppressed by amitriptyline (IC₅₀ = 0.0202 mM), fluoxetine (62% amplitude reduction at 0.02 mM), desiparmine (50% at 0.02 mM) and trazodone (20% at 0.1 mM; ^[229]). Amitriptyline also reduced Na⁺-channel current amplitudes in rat clonal pituitary GH₃ cells with an IC₅₀ value of 0.0398 mM ^[156]. These efficacies for Na⁺-channel inhibition were much larger than those of frog sciatic nerve CAPs. Furthermore, IC₅₀ value (0.0221 mM) for duloxetine to inhibit (TTX-sensitive) Nav1.7 channels was about 10-fold less than that (0.23 mM) for frog sciatic nerve CAP inhibition ^[228], while the efficacy sequence for CAP inhibition (maprotiline > fluoxetine) was the same as that of the Nav1.7 channel, where IC₅₀ values for maprotiline, fluoxetine, desipramine and amitriptyline were 0.028, 0.074, 0.024 and 0.085 mM, respectively ^[236]. The observation that amitriptyline and duloxetine had a similar IC₅₀ value for frog sciatic nerve CAP inhibition was the same as that for cardiac-type Na⁺-channel inhibition ^[227]. TTX-resistant Na⁺ channel, possibly Nav1.8 channel, current amplitude in rat trigeminal ganglion neurons was also reduced by amitriptyrine with an IC₅₀ value of 0.00682 mM ^[237]. With respect to chemical structure, typical local anesthetics have hydrophilic and hydrophobic moieties that are separated by an intermediate amide or ester linkage (see ^[238] for review), while all of the antidepressants tested in the frog sciatic nerve, except for trazodone, have a hydrophilic amine group and a hydrophobic moiety containing benzene rings, both of which are linked by a straight chain hydrocarbon (see Fig. 1 in ^[33] for the chemical structures of six antidepressants tested). Such chemical structures may take a pivotal role in inhibiting Na⁺ channels. Table 1 summarizes IC₅₀values for antidepressants to inhibit frog sciatic nerve fast-conducting CAPs (see also ^[68]).

The antidepressants examined in the frog sciatic nerve are clinically used to alleviate chronic pain ^{[10][11][217][218][221][239][240]} and attenuate neuropathic pain in animal models. For example, duloxetine inhibited tactile allodynia (where pain is caused by a stimulus that does not normally elicit pain) and heat hyperalgesia (an abnormally increased sensitivity to pain) in neuropathic pain rat models ^[215]. Fluoxetine produced analgesia in streptozotocin-induced diabetic neuropathic pain mouse models ^[201]. Amitriptyline and desipramine were effective in attenuating pain in patients with diabetic neuropathy ^[200]. Maprotiline suppressed neuropathic pain produced by chronic constriction injury of the sciatic nerve in rats ^[241]. Trazodone depressed hyperalgesia in chronic constriction injury rat models ^[222]. The plasma concentrations of duloxetine, fluoxetine, amitriptyline, desipramine, maprotiline and trazodone used to clinically treat depression and neuropathic pain are, respectively, 0.09-0.3, 0.3-1.6, 0.36-0.90, 0.47-1.1, 0.72-1.4 and 2.2-4.3 μM ^[205][228]. These concentration values were much smaller than those of IC₅₀ for frog sciatic nerve CAP inhibition. The antidepressants may produce an antinociception only when applied locally to the nerve.

3.4. Adrenoceptor Agonists

Epidural and intrathecal administration of α₂ adrenoceptor agonists including clonidine and DEX (see ^[242] for review) results in antinociception in animals ^{[243][244][245]} and humans ^[246]. This is possibly owing to the inhibition produced by the agonists of glutamatergic excitatory transmission in spinal superficial dorsal horn neurons ^[247]. α₂ Adrenoceptor agonists combined with local anesthetics in spinal anesthesia lead to the extension of peripheral nerve block duration in animals ^{[248][249][250][251]} and humans (^{[252][253][254][255][256][257][258][259]}; see ^[260] for review). This is possibly due to a local vessel contraction produced by the agonists, leading to a decrease in the clearance of the anesthetics from the subarachnoid space ^[261][262]. Moreover, α₂ adrenoceptor agonists attenuate nerve AP conduction and therefore have a local anesthetic effect, contributing to enhanced local anesthetic effect ^[263]. For instance, clonidine not only suppressed excitatory transmission in rat spinal lamina II neurons ^[264][265] but also blocked AP conduction in peripheral nerves ^{[172][263][266]}. The latter action required a much higher concentration of clonidine than the former one. DEX as well as clonidine reportedly inhibited excitatory transmission in rat lamina II neurons ^[267]. Intracutaneous application of DEX or clonidine together with lidocaine into the back of guinea-pigs increased the extent of the local anesthetic effect of lidocaine ^[268]. Local wound infiltration with DEX added to another local anesthetic bupivacaine more effectively attenuated postoperative pain compared to bupivacaine alone in humans ^[269]. In addition to clonidine, DEX possibly has an inhibitory action on nerve AP conduction, because DEX is reported to suppress voltage-gated Na⁺-channels ^[146] (see below).

Frog sciatic nerve CAP peak amplitudes were reduced by DEX in a concentration-dependent manner in a range of 0.01-1 mM with an IC₅₀ value of 0.40 mM ^[34]. The DEX activity was not inhibited by α₂-adrenoceptor antagonists, yohimbine and atipamezole (^{[247][270][271][272]}; see ^[273][274] for review), although DEX exhibited a high affinity for α₂ adrenoceptors ^[242]. This result indicates no involvement of α₂ adrenoceptors in the DEX activity ^[34]. CAP peak amplitude reduction was also seen by other α₂-adrenoceptor agonist, oxymetazoline, which is more selective to α_2A than α_2B and α_2C (see ^[273][275] for review), and also by clonidine in a manner resistant to yohimbine. Oxymetazoline reduced CAP peak amplitude with an IC₅₀ value of 1.5 mM. Clonidine at 2 mM reduced CAP peak amplitude by about 20% ^[34]. This clonidine activity was different in extent from that (CAP amplitude reduction of 80% at 0.3 mM) reported by Starke et al. ^[172] for frog sciatic nerve CAPs, although a reason for this discrepancy was unknown. On the other hand, frog sciatic nerve CAPs were not affected by various adrenoceptor agonists, adrenaline, NA, α₁-adrenoceptor agonist phenylephrine and β-adrenoceptor agonist isoproterenol at 1 mM ^[34]. A similar clonidine-induced CAP inhibition has been reported in the rat sciatic nerve. Thus, CAPs originating from primary-afferent Aα and C fibers in the rat sciatic nerve were found to be suppressed by clonidine with IC₅₀ values of 2.0 and 0.45 mM, respectively ^[266].

The α₂-adrenoceptor agonists-induced CAP inhibition would be mediated by a suppression of voltage-gated Na⁺ and K⁺ channels involved in AP production. DEX reportedly reduced voltage-gated Na⁺ channel current amplitude in rat DRG neurons in a manner insensitive to yohimbine, although this type of Na⁺channels was resistant to TTX ^[146]. IC₅₀ value (0.058 mM) for this rat DRG neuron DEX activity was about 10-fold smaller than that (0.40 mM) for frog sciatic nerve CAP inhibition. The rat TTX-resistant Na⁺ channel current amplitude was also reduced by clonidine with an IC₅₀ value of 0.26 mM ^[146]. TTX-sensitive Na⁺ channel current amplitudes in DRG neuroblastoma hybridoma cell line ND7/23 cells were reduced by clonidine (IC₅₀ = 0.824 mM; ^[155]). It has been reported in NG108-15 neuronal cells that delayed-rectifier K⁺-channel current amplitudes are reduced by DEX with an IC₅₀ value of 0.0046 mM while TTX-sensitive Na⁺-channel current amplitudes are reduced by about 20% by DEX (0.01 mM) in a manner insensitive to yohimbine ^[276]. These differences in drug potency may be due to a difference in either Na⁺-channel types or animal species. Table 1 summarizes the actions of adrenoceptor agonists on frog sciatic nerve fast-conducting CAPs together with their IC₅₀values (see also ^[68]).

In clinical practice, DEX administration results in producing analgesia/sedation and decreasing heart rate, cardiac output and memory, each of whose effects depends on the plasma concentration of DEX in a different manner ^[277]. In patients, sedation is rapidly induced by 0.2 to 0.7 mg·kg^-1·hr^-1 i.v. ^[242]. In intramuscular application in cats, 40 mg·kg^-1 is a usual dose to produce analgesia/sedation ^[278]. DEX concentrations necessary to inhibit frog sciatic nerve AP conduction are >1000-fold higher than those of the usage of DEX as α₂ adrenoceptor agonist, because the clinical usage of DEX is < 0.05 μM for plasma levels (see ^[277]). Therefore, the DEX’s potency in blocking nerve AP conduction is independent of the usage of DEX for analgesia/sedation. α₂-Adrenoceptor agonists including DEX, combined with a local anesthetic, have been used to extend peripheral nerve AP conduction block duration ^{[249][252][253][254][255][279]}. It is possible that this effect is mediated by a local vasoconstriction leading to a delay of the absorption of the local anesthetic and/or a direct nerve AP conduction suppression produced by α₂ adrenoceptor agonists ^[256]. The latter mechanism would be the above-mentioned nerve CAP inhibition produced by α₂ adrenoceptor agonists. This action makes sense when considering their topical administration on nerves, but is not related to their usage for analgesia/anesthesia by systemic application. A chemical structure related to their α₂ adrenoceptor agonists (see ^[34]) may play a crucial role in producing nerve AP conduction blockage.

Comparison in Nerve AP Conduction Inhibition among Analgesics and Analgesic Adjuvants

4. Comparison in Nerve AP Conduction Inhibition among Analgesics and Analgesic Adjuvants

As noted from Table 1, some of analgesic adjuvants had similar IC₅₀ values for frog sciatic nerve CAP inhibitions. For example, antidepressants had IC₅₀ values similar to those of some of local anesthetics, antiepileptics and α₂-adrenoceptor agonists. Duloxetine and amitriptyline values (0.23 and 0.26 mM, respectively) were similar to those of ropivacaine, levobupivacaine, pramoxine, lamotrigine, carbamazepine and DEX (0.34, 0.23, 0.21, 0.44, 0.50 and 0.40 mM, respectively). On the other hand, fluoxetine, desipramine, maprotiline and trazodone values (1.5, 1.6, 0.95 and ca. 1 mM, respectively) were similar to those of lidocaine, cocaine, procaine, prilocaine and oxymetazoline (0.74, 0.80, 2.2 and 1.8 and 1.5 mM, respectively). There was not a common chemical structure among the former (IC₅₀: 0.2-0.5 mM) or latter (IC₅₀: 0.7-2 mM) drugs, although the number of CH₂ in opioids having similar structures was related to the extent of CAP inhibition (see Section 2.2). The antidepressants had IC₅₀ values being much larger than that of tetracaine (0.014 mM). Thus, some of the analgesic adjuvants will have an ability to inhibit nerve AP conduction with an efficacy comparable to each other.

When IC₅₀values of analgesic adjuvants were compared with those of antipyretic analgesics NSAIDs, diclofenac’s IC₅₀ value (0.94 mM) was close to those of lidocaine, cocaine, maprotiline and trazodon, (0.74, 0.80, 0.95 and ca. 1 mM, respectively), while aceclofenac, tolfenamic acid, meclofenamic acid and flufenamic acid (0.47, 0.29, 0.19 and 0.22 mM, respectively) had IC₅₀ values being similar to those of ropivacaine, levobupivacaine, pramoxine, duloxetine, amitriptyline, lamotrigine, carbamazepine and DEX (0.34, 0.23, 0.21, 0.23, 0.26, 0.44, 0.50 and 0.40 mM, respectively). The NSAIDs’ values were smaller than those of procaine, prilocaine, fluoxetine, desipramine and oxymetazoline (2.2, 1.8, 1.5, 1.6 and 1.5 mM, respectively), while being larger than that of tetracaine (0.014 mM). Thus, NSAIDs could suppress nerve AP conduction with efficacies comparable to some of analgesic adjuvants. In these cases, there were no common chemical structures among compounds having similar IC₅₀ values.

Not only NSAIDs and analgesic adjuvants but also narcotic analgesics opioids have an ability to inhibit nerve AP conduction. Frog sciatic nerve CAP peak amplitudes were also reduced by opioids; tramadol and ethylmorphine had the IC₅₀ values of 2.3 and 4.6 mM, respectively; morphine and codeine at 5 mM reduced CAP amplitude by 15% and 30%, respectively. These opioid actions were smaller in extent than those of NSAIDs and analgesic adjuvants. For instance, the IC₅₀ value (2.3 mM) of tramadol was larger by 3.1- and 6.8-fold than those (0.74 mM and 0.34 mM, respectively) of lidocaine and ropivacaine, respectively ^[27]. Lidocaine is previously reported by other investigators to reduce frog sciatic nerve CAP amplitudes with an IC₅₀ of 6.6 mM, a value larger by three-fold than the tramadol value ^[107]. Ratio of the IC₅₀ value of tramadol to that of lidocaine was almost comparable to Katsuki et al. ^[27]’s one, albeit IC₅₀ values for lidocaine were largely different between the two studies ^[27][107]. A contribution of nerve AP conduction inhibition to analgesia produced by opioids appears to be much less in extent compared to well-known other cellular mechanisms including a membrane hyperpolarization and a decrease in the release of L-glutamate from nerve terminals in the spinal dorsal horn (for instance, see ^[74][75]). In conclusion, nerve AP conduction suppression may be a common mechanism for antinociception produced by NSAIDs and analgesic adjuvants but not opioids.

IC₅₀ values for the analgesic adjuvants to inhibit frog sciatic nerve CAPs were similar to those in rat sciatic nerve CAPs while being generally larger than IC₅₀ values for TTX-sensitive Na⁺ channel inhibitions. This difference could be explained by several possibilities. First, CAPs are produced by not only voltage-gated Na⁺ but also K⁺ channels. Second, TTX-sensitive Na⁺-channel types (Nav1.1-1.4, Nav1.6 and Nav1.7) may differ in expression among the preparations examined. Third, CAPs originate from a bundle of nerve fibers while Na⁺ currents from single cells. When the analgesic adjuvants used clinically act on the nerve trunk, their sciatic nerve IC₅₀ values may be an appropriate measure for a nerve AP conduction inhibition in vivo, because nerve conduction is mediated by both voltage-gated Na⁺ and K⁺ channels. Considering that nociceptor-specific deletion of TTX-sensitive Nav1.7 gene results in inhibited acute and inflammatory pain in mice ^[280], Na⁺ channels may be the main target of analgesics and analgesic adjuvants.

Actions of Plant-Derived Compounds on Nerve AP Conduction

5. Actions of Plant-Derived Compounds on Nerve AP Conduction

Many of plant-derived compounds activate TRP channels located in the peripheral terminals of primary-afferent Aδ-fiber and C-fiber neurons, resulting in the production of AP, which in turn leads to temperature sensation and nociception. For example, capsaicin, allyl isothiocyanate and menthol activate TRPV1, TRPA1 and TRP melastatin-8 (TRPM8) channels, respectively (for example, see ^{[15][281][282]} for review). On the other hand, TRPV1, TRPA1 and TRPM8 channels are expressed in primary-afferent neuron central terminals in lamina II of the spinal dorsal horn, and the central terminal TRP channels are activated by various plant-derived compounds such as capsaicin, allyl isothiocyanate, menthol, eugenol, carvacrol, thymol, (-)-carvone, (+)-carvone, 1,4-cineole, 1,8-cineole, (±)-linalool and geraniol (^{[283][284][285][286][287][288][289][290]}; see ^[291][292] for review). This activation is thought to be involved in the modulation of excitatory and inhibitory synaptic transmission in lamina II neurons, resulting in nociceptive transmission modulation. This idea is supported by the observation that synaptic transmission in lamina II neurons is affected by a variety of endogenous pain modulators (for example, see ^[17] for review).

As with analgesics and analgesic adjuvants, CAPs in the frog sciatic nerve were inhibited by many of plant-derived compounds that produce antinociception by their topical, oral, intraperitoneal or intrathecal administration (see ^[293][294] for review). Carvacrol, thymol, citronellol, bornyl acetate, citral, citronellal, geranyl acetate and geraniol reduced frog sciatic nerve CAP peak amplitudes with the IC₅₀ values of 0.34, 0.34, 0.35, 0.44, 0.46, 0.50, 0.51 and 0.53 mM, respectively (Table 1). Although capsaicin’s IC₅₀ value was not able to be evaluated owing to its less solubility, capsaicin at 0.1 mM reduced CAP peak amplitudes by 36% (Table 1); this action could be attributed to at least a part of alleviation of chronic pain produced by capsaicin applied to the skin (^[295][296]; for example, see ^[15] for review). Their plant-derived compounds’ activities were close to those of analgesic adjuvants and NSAIDs (^{[32][297][298][299]}； see ^[35] for review). Thus, their IC₅₀ values were comparable to those of duloxetine (0.23 mM), amitriptyline (0.26 mM), aceclofenac (0.47 mM), tolfenamic acid (0.29 mM), meclofenamic acid (0.19 mM) and flufenamic acid (0.22 mM). Furthermore, (+)-pulegone, (-)-carvone, (+)-carvone, (+)-borneol, (±)-linalool, (-)-menthone, (+)-menthone, (-)-carveol, α-terpineol, rose oxide, cinnamaldehyde and allyl isothiocyanate attenuated frog sciatic nerve CAP peak amplitudes with the IC₅₀ of 1.4, 1.4, 2.0, 1.5, 1.7, 1.5, 2.2, 1.3, 2.7, 2.6, 1.2 and 1.5 mM, respectively (Table 1); these values were similar to those of fluoxetine (1.5 mM) and desipramine (1.6 mM). Linalyl acetate, eugenol, (-)-menthol and (+)-menthol had the IC₅₀ values of 0.71, 0.81, 1.1 and 0.93 mM, respectively (Table 1); these values were close to those of diclofenac, maprotiline and trazodone (0.94, 0.95, and ca. 1.0 mM, respectively).

The cinnamaldehyde and allyl isothiocyanate activities were resistant to a non-selective TRP antagonist ruthenium red, indicating no involvement of TRP channels ^[298]. Capsaicin at high concentrations (0.03-0.1 mM) inhibited voltage-gated Na⁺-channels in rodents in a manner independent of TRPV1 channels ^{[300][301][302]}. Other plant-derived compounds-induced CAP inhibitions are possibly mediated by an attenuation of TTX-sensitive voltage-gated Na⁺ channels (for example, eugenol ^[303], thymol ^[304], carvacrol ^[305] and linalool ^[306]; see ^[307] for review). IC₅₀ value (0.37 mM) for inhibition by carvacrol of voltage-gated Na⁺ channels in rat DRG neurons ^[308] was very similar to that (0.34 mM) for the frog sciatic nerve CAP inhibition.

Some plant-derived compounds had weak inhibitory effects on frog sciatic nerve CAPs. For example, 1,8-cineole, 1,4-cineole, zingerone, guaiacol and vanillin had IC₅₀ values of 5.7, 7.2, 8.3, 7.7 and 9.0 mM, respectively. p-Cymene (2 mM), myrcene (5 mM), vanillylamine and (+)-limonene (each 10 mM) reduced CAP peak amplitudes by 22, 7, 12 and 8%, respectively; vanillic acid (7 mM), p-menthane and menthyl chloride (each 10 mM) had no effect on CAPs (Table 1). Their compounds’ activities were much smaller than those of NSAIDs and analgesic adjuvants. In conclusion, some plant-derived compounds could be used instead of NSAIDs and analgesic adjuvants in terms of nerve AP conduction inhibition. Plant-derived compounds will be expected to have side effects less than synthetic analgesics.

Although the above-mentioned plant-derived compounds have open chains or six-membered rings, a seven-membered ring compound hinokitiol (β-thujaplicin; 2-hydroxy-4-isopropylcyclohepta-2,4,6-trien-1-one; contained in a species of cypress tree ^[309]) also reduced frog sciatic nerve CAP peak amplitudes with an IC₅₀ value of 0.54 mM (Table 1). This value was comparable to those of many other plant-derived compounds. The CAP inhibition is possibly mediated by an interaction involving the carbonyl, isopropyl and hydroxyl groups of hinokitiol ^[310]. The carbonyl group serves for the seven-membered ring of hinokitiol to act as a benzene ring, while the isopropyl and hydroxyl groups are important for the CAP amplitude reduction produced by hinokitiol. This idea is supported by the observation that benzene-ring compounds having the isopropyl and hydroxyl groups, such as thymol, carvacrol, biosol (the last of which is a stereoisomer of thymol and carvacrol; IC₅₀ = 0.58 mM), and also 4-isopropylphenol (0.85 mM) had an ability to suppress frog sciatic nerve CAPs (see above; ^[297][310]). As with other plant-derived compounds, hinokitiol has a variety of actions including inhibition of apoptosis ^[311], anti-bacterial, anti-inflammatory ^[312], insecticidal ^[313], anti-fungal ^[314], anti-tumor ^[315] and cytotoxic activities ^[316][317]. Hinokitiol used as a dermatological drug to inhibit inflammation may have a local anesthetic effect. Application of an oral care gel containing hinokitiol to the oral mucosa is reported to alleviate oral pain in patients with oral lichen planus related to hepatitis C virus infection ^[318]. Such a pain attenuation may be partly mediated by a local anesthetic effect of hinokitiol

A CAP inhibitory action similar to hinokitiol was seen with a general anesthetic propofol (2,6-diisopropylphenol; ^{[319][320][321]}; see ^[322][323] for review) having two isopropyl groups and one hydroxyl group bound to the benzene ring. Thus, propofol reduced frog sciatic nerve CAP peak amplitudes in a concentration-dependent manner with an IC₅₀ of 0.14 mM, a value smaller than that of hinokitiol (Table 1; ^[30]). Consistent with this observation, propofol reportedly suppressed APs recorded extracellularly in the human and mammalian CNS ^[324][325]. Such an inhibitory action of propofol on nerve AP conduction may contribute to its antinociceptive effect together with a propofol-induced enhancement of GABA_A-receptor responses in lamina II neurons ^[326].

Traditional Japanese (Kampo) medicines composed of plant-derived crude chemicals are used together with Western medicines in Japan with various purposes such as antinociception (see ^{[327][328][329][330][331][332]} for review). Daikenchuto is one of most frequently-prescribed Kampo medicines and is used to treat cold sensation and dysmotility in the abdomen. Frog sciatic nerve CAP amplitudes were reduced by daikenchuto and also by other Kampo medicines, rikkosan, kikyoto, rikkunshito, shakuyakukanzoto and kakkonto in a concentration-dependent manner. Among these medicines, daikenchuto was the most effective with an IC₅₀ value of 1.1 mg/mL. Daikenchuto has three kinds of crude medicine, Japanese pepper, processed ginger and ginseng radix, the former two of which suppressed CAPs while the last had no effects on CAPs. Japanese pepper had an IC₅₀ value of 0.77 mg/mL and processed ginger at 2 mg/mL reduced CAP peak amplitudes by 31% ^[333]. A small part of the analgesic effect of Kampo medicine may be due to its nerve AP conduction inhibitory action.

Table 1.

Effects of analgesics, analgesic adjuvants and plant-derived compounds on fast-conducting CAPs recorded from the frog sciatic nerve.

(1) NSAIDs ^[26]

(a) Acetic acid-based NSAIDs

Diclofenac Aceclofenac Indomethacin Acemetacin Etodolac Sulindac Felbinac

0.94 mM 0.47 mM 38% reduct. 38% reduct. 15% reduct. No effect No effect

(1 mM) (1 mM) (1 mM) (1 mM) (1 mM)

(b) Fenamic acid-based NSAIDs

Tolfenamic acid Meclofenamic acid Mefenamic acid Flufenamic acid

0.29 mM 0.19 mM 16% reduct. (0.2 mM) 0.22 mM

Aspirin

No effect (1 mM)

(d) Propionic acid-based NSAID

Ketoprofen Naproxen Ibuprofen Loxoprofen Flurbiprofen

No effect (1 mM) No effect (1 mM) No effect (1 mM) No effect (1 mM) No effect (1 mM)

(e) Enolic acid-based NSAID

Meloxican Piroxicam

No effect (0.5 mM) No effect (1 mM)

(2) Opioids ^[27][28]

Tramadol Mono-O-desmethyl-tramadol Morphine Codeine Ethylmorphine

2.3 mM 9% reduct. (5 mM) 15% reduct. (5 mM) 30% reduct. (5 mM) 4.6 mM

(3) Local anesthetics ^{[27][28][29][30][31][32]}

(a) Amide-type local anesthetics

Lidocaine Ropivacaine Prilocaine Levobupivacaine Bupovacaine

0.74 mM 0.34 mM 1.8 mM 0.23 mM 76% reduct. (0.5 mM)

(b) Ester-type local anesthetics

Cocaine Procaine Benzocaine Tetracaine

0.80 mM 2.2 mM 0.80 mM 0.014 mM

Pramoxine

0.21 mM

(4) Antiepileptics ^[29]

Lamotrigine Carbamazepine Oxcarbazepine Phenytoin Gabapentin Topiramate Sodium valproate

0.44 mM 0.50 mM 20% reduct. 15% reduct. No effect No effect No effect

(0.5 mM) (0.1 mM) (10 mM) (10 mM) (10 mM)

(5) Antidepressants ^[33]

Duloxetine Fluoxetine Amitriptyline Desipramine Maprotiline Trazodone

0.23 mM 1.5 mM 0.26 mM 1.6 mM 0.95 mM ca.1.0 mM

(6) Adrenoceptor agonists ^[34]

Adrenaline Noradrenaline Dexmedetomidine Oxymetazoline Clonidine Phenylephrine Isoproterenol

No effect No effect 0.40 mM 1.5 mM ca. 20% reduct. No effect No effect

(1 mM) (1 mM) (2 mM) (1 mM) (1 mM)

(7) Plant-derived compounds

(a) Open chain or six-membered ring compounds ^{[32][297][298][299]}

Carvacrol Thymol Citronellol Bornyl acetate Citral Citronellal Geranyl acetate Geraniol

0.34 mM 0.34 mM 0.35 mM 0.44 mM 0.46 mM 0.50 mM 0.51 mM 0.53 mM

Capsaicin (+)-Pulegone (-)-Carvone (+)-Carvone (+)-Borneol (±)-Linalool

36% reduct. (0.1 mM) 1.4 mM 1.4 mM 2.0 mM 1.5 mM 1.7 mM

(-)-Menthone (+)-Menthone (-)-Carveol α-Terpineol Rose oxide Cinnamaldehyde Allyl isothiocyanate

1.5 mM 2.2 mM 1.3 mM 2.7 mM 2.6 mM 1.2 mM 1.5 mM

Linalyl acetate Eugenol (-)-Menthol (+)-Menthol 1,8-Cineole 1,4-Cineole Zingerone Guaiacol

0.71 mM 0.81 mM 1.1 mM 0.93 mM 5.7 mM 7.2 mM 8.3 mM 7.7 mM

Vanillin p-Cymene Myrcene Vanillylamine (+)-Limonene

9.0 mM 22% reduct.(2 mM) 7% reduct. (5 mM) 12% reduct. (10 mM) 8% reduct. (10 mM)

Vanillic acid p-Menthane Menthyl chloride

No effect (7 mM) No effect (10 mM) No effect (10 mM)

(b) Seven-membered ring compound ^[310]

Hinokitiol

0.54 mM

(8) General anesthetic [30]

Propofol

0.14 mM

Here, IC₅₀ value for CAP inhibition and the extent of CAP amplitude reduction (reduct.) at each concentration are shown.

6. Conclusion

Conclusion

This revisew article arch demonstrated that frog sciatic nerve CAPs are depressed by some of NSAIDs, analgesic adjuvants and plant-derived compounds having analgesic activities with similar efficacies and also by opioids with efficacies less than them. Although the CAPs are originated from fast-conducting TTX-sensitive Aα fibers, nociceptive information is transferred through slow-conducting Aδ and C fibers ^[1]. Slow-conducting CAPs were not able to be recorded from the frog sciatic nerve, because Aδ-fiber CAPs were not able to be isolated from Aα-fiber ones and C-fiber CAPs were much smaller in peak amplitude and conduction velocity than fast-conducting Aα ones ^[25]. Therefore, the effects of the antinociceptive compounds on slow-conducting CAPs were not able to be examined. In order to know a detail of differences in nerve AP conduction inhibition extent among various antinociceptive compounds, it would be necessary to examine their effects on slow-conducting CAPs.

In nerves other than the frog sciatic nerve, antinociceptive drugs reportedly suppress not only A-fiber but also C-fiber CAPs. For instance, in the rabbit vagus nerve, fentanyl and sufentanil inhibited C-fiber CAPs with extents smaller than those of A-fiber ones ^[86] and lidocaine blocked nerve AP conduction in not only myelinated A-fibers but also unmyelinated C-fibers (^[334]; lidocaine inhibited more effectively rat A-fiber CAPs than C-fiber ones ^[335]). Clonidine inhibited both Aα-fiber and C-fiber CAPs (see Section 3.4). Furthermore, many researchers have demonstrated a suppression by NSAIDs ^{[58][65][336]}, lidocaine and α₂-adrenoceptor agonists ^[146] of TTX-resistant voltage-gated Na⁺ channels that may be involved in slow-conducting CAP production. Knockdown of TTX-resistant Nav1.8 channels reportedly results in inhibition of neuropathic and inflammatory pain in rats ^[337].

Since analgesic and analgesic adjuvant concentrations needed for CAP inhibition are higher than clinically relevant ones, as mentioned above, nerve AP conduction inhibition may occur only when the drugs are applied locally or are accumulated in the nervous system. If such a suppression occurs in Aα fibers innervating skeletal muscle, this would result in undesirable side effects such as muscle paralysis. Thus, the drugs will have to be used at the lowest possible concentrations. Primary-afferent C and Aδ fibers are smaller in diameter than Aα ones. Therefore, if the drugs act on voltage-gated Na⁺ channels from cytoplasm side, C fibers will precede Aα fibers in attenuating nerve AP conduction due to a distinction in surface-to-volume ratio between the fibers. At least a part of antinociception produced by analgesics and analgesic adjuvants could be attributed to their inhibitory actions on nerve AP conduction mediated by the activation of voltage-gated TTX-sensitive and TTX-resistant voltage-gated Na⁺ channels.

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