Actions of Analgesics on Nerve Conduction: Comparison
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The aAction potential (AP) conduction in nerve fibers plays a crucialn important role in transmitting nociceptive information from the periphery to the cerebral cortex. Nerve AP conduction inhibition  It is possibly results in analgesia. It is well-known that many anae that analgesics suppdepress nerve AP conduction and voltage-dependent sodium and potassium channels that are involved in producing APs. The compound action potential (CAP) recorded from a bundle of nerve fibers is a guide for knowing if analgesics affect , resulting in antinociception.  Many of analgesics are known to suppress nerve AP conduction. This entry mentions the inhibitory effects of clinically used analgesics, analgesic adjuvants, and plant-derived analgesics on fast-conducting CAPs and voltage-dependent sodium and also voltage-sensitive Na+ and potassiumK+ channels. The efficacies of their effects were compared among the compounds, and it was revealed that some of the coinvolved in AP conduction. Compounds have similar efficacies in suppressing CAPs. It is suggested that analgesics-induced action potential (CAP) has been used to know whether nerve AP conduction inhibition may contribute to at least a part of their as affected by analgesic effects.

  • antinociception
  • analgesic
  • analgesic adjuvant
  • plant-derived compound
  • nerve conduction
  • sciatic nerve
  • compound action potential
  • sodium channel
  • potassium channel
  • Na+ channel
  • K+ channel
S

1. Introduction

Nociceptive ignal of painful stimuli apformation from the periphery to the cerebral cortex is mainly transmitted by action potential (AP) conduction in nerve fibers and chemical transmission at synapses (see [1][2] for reviews). Nociceptive pain is usuallied to the skin is mainly conveyed by primary-afferent thin myelinated Aδ-fibers and unmyelinatedy acute and relieved by narcotic analgesics such as opioids and antipyretic analgesics including non-steroidal anti-inflammatory drugs (NSAIDs). On the other hand, pain may persist or recur for longer than three months, which is called chronic pain. One type of chronic pain, neuropathic pain, which occurs as a result of damage to the peripheral or central nervous system (PNS and CNS, respectively), is characterized by a hyper-excitability of neurons near the injured neuronal tissues (see [3] C-fibers to the spinal cord and brain stor review). This type of pain is often resistant to analgesics such as opioids and NSAIDs and is thus treated by using analgesic adjuvants such as α2-adrem;noceptor agonists, the inantiepileptics, antidepressants and local anesthetics (see [4][5][6][7][8][9][10][11] for reviews). Although the mation is then transmin target of analgesics and analgesic adjuvants, except for NSAIDs and local anesthetics, is generally synapses (see [12][13][14] for reviews), itt is possibled to the brain by t that all of their drugs inhibit nerve AP conduction, partly contributing to their inhibitory effects on pain.
The AP conduction of is mediated by voltage-gated Na+ and K+ channels location potentiaed in nerve fibers. Thus, a depolarizing stimulus given to a nerve fiber point activates Na+ channels (APexpress) in nerved in membranes of the fiber, allowing Na+ entry to the cytoplasm, and caused by the gradient of the electrochemical tpotential of Na+, leading to a self-regeneransmission at neuron-to-neuron junctiontive production of AP. This in turn results in an outward current (membrane depolarization) in a fiber point adjacent to the point to produce opening of other Na+ channels and so [1][2][3][4]forth. ASucute nocih a production of AP subsides by a subsequent inactivation of Na+ channeptive pain ls and activation of K+ chausennels (see [15][16] for reviews).
In a bundle by tissue injury or damage is a physiological mechanismof nerve fibers exposed to insulator such as oil, sucrose or air, AP conduction in each fiber produces AP current flowing through nerve bundle surface having high resistance that serves to protect a person against injury, which is usually acan be measured as a potential difference, i.e., compound action potential (CAP), by using two electrodes put on the nerve. Sciatic nerve trunk dissected from frogs is a useful preparation to easily and stably record voltage-gated Na+-channel bleviated by antipyretiocker tetrodotoxin (TTX)-sensitive and fast-conducting (possibly myelinated Aα-fiber mediated) CAPs by using the nerve trunk exposed to air (air-gap method). A voltage-gated delayed-rectifier K+-channel analgesics including non-inhibitor tetraethylammonium increased the half-peak duration of the CAP with no change in its peak amplitude, indicating an involvement of K+ channels (stee [17] for review). Althoidal anti-inflammatory drugs (NSAIDs) and narcotic anugh not only fast-conducting but also slow-conducting (C-fiber mediated) CAPs were recorded from the frog sciatic nerve, the latter had much smaller peak amplitude and conduction velocity than the former [18].

2. Actions of Analgesics on Nerve Conduction

2.1. Opioids

Opioids are welgesics such as l-known to inhibit glutamatergic excitatory transmission by activating opioids. O receptors in the other hand, chronic pain, which mayCNS including the central terminals of primary-afferent fibers, resulting in antinociception ([19][20][21]; lastee [22][23] for reviews). Not only centra long time, such as three monthl but also peripheral terminal opioid receptors in primary-afferent neurons are thought to be involved in antinociception ([24][25][26][27]; see [28] for more, or occur repeatedly, is a debilitating disease aview). Opioids also exhibit a local anesthetic effect in the PNS. Although it has been reported in decerebrated cats that the perineural administration of an opioid morphine has no effect on CAPs in the superficial radial nerve [29], AP conducompanied by spontaneous pain, etc. and is often restion in peripheral nerve fibers is generally blocked by opioids. For example, opioids such as fentanyl and sufentanil decreased the peak amplitudes of CAPs recorded from peripheral nerve fibers [30] and inhibistanted peripheral nerve AP conduction [31]. A morphine-induced CAP inhibitio analgesics such as NSAIDs andn in mammalian peripheral nerve fibers was antagonized by a non-specific opioid-receptor antagonist naloxone, indicating an involvement of opioids receptors [32]. NConsisteuropathic pain, which is one type of chronic paint with this observation, binding and immunohistochemical studies have shown the localization of opioid receptors in mammalian peripheral nerve fibers [33][34][35]. It has been, also results from a direct injury givendemonstrated that a frog sciatic nerve CAP inhibition produced by opioids is sensitive to naloxone [36]. On the co the peripheralntrary, there are reports showing that opioids decrease CAP peak amplitudes [30] and supprervousss nerve AP conduction [31] in a manner resysteistant to naloxone.

2.1.1. Tramadol

The compound (PNS1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexand damage caused in theol hydrochloride (tramadol) is an orally-active opioid which is clinically used as an analgesic in the CNS [37]. cenAlthough tral nervous smadol is metabolized to various compounds such as mono-O-desmethysltem (CNS),ramadol (M1) via N- and O-demethylatiton in is chaanimals and humans [38], M1 is a therapeuticterized by an exally active drug as a central analgesic [37]. One of cellular mechanissive rise in tms for the antinociceptive effect of tramadol is the activation of μ-opioid receptors [39][40]. In agreement with this ide excitability of neurons in the vicinity of injured or damaged neuronal tissuesa, M1 has the highest affinity for cloned μ-opioid receptors among the metabolites of tramadol. M1 is reported to inhibit glutamatergic excitatory transmission in spinal lamina II (substantia gelatinosa) [5].neurons Twhis type of pain is alleviated by using analgesicch play a crucial role in regulating nociceptive transmission to the spinal dorsal horn from the periphery, resulting in a decrease in the excitability of the neurons [41][42][43]. In addjuvantsition to such as a central activity, tramadol is known to have a local anesthetics, antiepileptics, antidepressants, and α2-adr effect following its intradermal injenoceptor agonistion in patients ([644][745][846]; see [947][10][11][12][13][14][15] for review). AConsistent with this resulthough analgesics and analgesic, in vivo studies have shown a spinal somatosensory evoked potential inhibition produced by a direct application of tramadol to the rat sciatic nerve [48]. Tramadjuvants generally depreol reduced the peak amplitude of CAPs recorded from the frog sciatic nerve in a concentration-dependent manner in a range of 0.2 to 5 mM [49]. A ssimilar CAP excitatory synaptic trinhibitory action of tramadol has been reported by other investigators in the frog [50] and rat smissionciatic nerve [1651][1752][18],. Analysis based on the Hill mequany of theition demonstrated that half-maximal inhibitory concentration (IC50) value for tramadrugs can possiol to reduce frog sciatic nerve CAP amplitudes is 2.3 mM; this IC50 value was smaller bly suppressabout three-fold than that (6.6 mM) reported previously for the frog sciatic nerve [50]. Rat sciatic nerve CAPs conwere inhibited by tramadol (37% peak amplitude reduction, whic at 4 mM) less effectively than frog sciatic nerve’s ones [51]. This in part contributes to their inhibitorhibitory action of tramadol in the frog sciatic nerve was not affected by the pretreatment of the sciatic nerve with naloxone (0.01 mM); a μ-opioid receptor agonist (D-Ala2, N-Me-Phe4, Gly5-ol)enkephalin (DAMGO; 1 μM) had no effects on pain. Plants and their con on frog sciatic nerve CAPs. Furthermore, CAPs were affected by much smaller extents by M1 (see below) that is similar in chemical structure to tramadol while exhibiting a higher affinity for μ-opioid receptors than tramadol [53]. These resultituents ares indicate that the tramadol-induced CAP inhibition is not mediated by opioid receptors [49]. Consistent with this result, a sed as folk remedies to pinal somatosensory evoked potential inhibition following the application of tramadol on rat sciatic nerves in vivo was resistant to naloxone [48]. Although tramadol inhibits noradrenalieve pain as a drugne (NA) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at concentrations similar to those that activate μ-opioid receptors [54][55], a wcombith few side effectsnation of inhibitors of the reuptake of NA and 5-HT (desipramine and fluoxetine, respectively; each 10 μM) did not affect frog sciatic [19][20][21].
nerve CAPs, conduction isindicating no involvement of NA and 5-HT reuptake inhibition in the CAP inhibition [49]. The CAP inhibition produced by thramadol is possibly due activa to an inhibition of voltage-dgated Na+ and K+ channepls involvendent sodium and potd in the production of AP. Tramadol concentration-dependently reduced the peak amplitude of TTX-sensitive Na+ channel currents recorded from dorsium chanal root ganglion (DRG) neuroblastoma hybridoma cell line ND7/23 cells with an IC50 value of 0.194 mM [56] and from HEK293 cells expressed in ing rat Nav1.2 channels with an IC50 value of 0.103 mM [57]. These values were smaller than that (2.3 mM) for frog sciatic nerve fibers. Thu CAP inhibition. It has been demonstrated that tramadol suppresses the current amplitude of delayed rectifier K+-channels (Kv3.1a type) expressed in NG 108-15 cells with an IC50 of 0.025 mM, a value much lesstim than 2.3 mM [58]. Such IC50 values that infor tramadol to inhibit CAPs, Na+ andu K+ channes membrals were higher than its clinically relevant concentration of about 2 μM in serum [43][59]. Unlike depolarization, atramadol, M1 (1-2 mM) did not affect frog sciatic nerve CAPs. This was confirmed in the frog sciatic nerve whose CAPs were inhibited by tramadol (1 mM; [49]). CAP peak amplied to a certain point on a nerve fiber, opens a sodium channel,tudes were reduced by 9% by M1 at 5 mM. Consistent with such smaller effects of M1, APs conducting on rat primary-afferent fibers were not blocked when the effect of M1 (1 mM) on dorsal root-evoked excitatory postsynaptic currents was examined by applying the patch-clamp technique to lamina II neurons in spinal cord slices [42]. It is interesting to note that tramadol has -OCH3 boulnd to ting in an influx of sodium ion into he benzene ring while M1 has -OH and thus that the methyl group is present in tramadol but not M1. This result indicates that the difference in chemical structure between tramadol and M1 is responsible for the distinction in CAP inhibition (see Figure 5a in [49] for a comparison of the chelmical structures of the two compounds).

2.1.2. Other Opioids

In order to reveal whether such according to th structure-activity relationship is seen for other opioids, the effects of morphine, codeine and ethylmorphine on frog sciatic nerve CAPs were examined. Morphine concentration and -dependently reduced CAP peak amplitude; this extent at 5 mM was 15%. Codeine, which has -OCH3 in place otentiaf -OH in morphine, at 5 mM reduced CAP peak amplitude by 30%. Moreover, CAPs were more effectively inhibited by ethylmorphine, where -OH of morphine is replaced by -OCH2CH3; amplitude gradient acreduction at 5 mM was 61%. IC50 value for ethylmoss the cell membranerphine in reducing CAP peak amplitudes was 4.6 mM. CAP inhibitions produced by morphine (10 mM), codeine (5 mM) and ethylmorphine (2 mM) were resistant to naloxone (0.01 mM). Naloxone at a high concentration such as 1 mM by itself reduced by 9% CAP peak amplitudes, but did not affect morphine (10 mM) activity [60]. Thies leads to AP e results indicate no involvement of opioid receptors in the CAP inhibition production in a sed by opioids, as reported previously in mammalian peripheral nerves [30][31][61]. A sequelnce of-renewing manner, which in t the opioid-induced CAP peak amplitude reduction was ethylmorphine > codeine > morphine. Thus, CAP amplitude reduction increased in extent with an increase in the number of -CH2 (see Figure 7A in [60] for a compauses an outward rison of the chemical structures of the three opioids). This result is consistent with the above-mentioned observation that tramadol having -OCH3 in the benzene ring inhibits CAPs more effecutively than M1 which is different from tramadol only in terrent, i.e., membrane depolarization, to open other sms of the presence of -OH in the ring. Interestingly, this result was obtained in spite of the fact that the chemical structures of morphine, codeine and ethylmorphine are quite distinct from those of tramadol and M1 (see [62] fodr revium chanew). Since the increase in -CH2 numbels at the points next to it. Such an AP pror is thought to enhance lipophilicity of opioids, lipophilic opioid-channel interaction is suggested to play a pivotal role in nerve AP conduction iblock, as shown for local anesthetics [63][64]. Thisubs ided by subsequent sodium channel inactivation and potassium ca is supported by the observation that the potency in CAP inhibition in the rat sciatic nerve was in the order of isopropylcocaine (where the methyl ester group of cocaine is replaced with an isopropyl ester group) > cocaethylene (where its methyl ester group is replaced with an ethyl ester group) > cocaine [65]). It is interesting to note that the sequennel openingce of the affinity of opioids for μ-opioid receptors is morphine > codeine > ethylmorphine [2266][23].

Isolation Methods for Testing Analgesic Action on Nerve Fibers

T, the order of which istudy of AP in mammals is complic reversed to one for CAP inhibition. If the opioid-induced inhibition of CAPs is mediated by the need to dissect out individualμ-opioid receptors, CAP inhibition sequence will be expected to be morphine > codeine > ethylmorphine. However, this sequence is not seen, a result being consistent with the idea that the opioids-induced frog sciatic nerves to isolate t CAP inhibition is not mediated by opioid receptors. The sam from periphere sequence as that in the frog sciatic nerve has been reported in the rat phrenic nerve [61], although stimulation. For this reason, neuroscience relies on nerve extrthere is a quantitative difference between the two studies. When compared at 5 mM, codeine-induced reduction (about 30%) in frog sciatic nerve CAP peak amplitude was much smaller than that (about 70%) in the rat phrenic nerve, while so a large distinction was not seen in morphine action from relat(about 10%). Frog sciatic nerve CAPs were less sensitive to morphine than those in rabbit and guinea-pig vagus nerves in such that vagus nerve CAP peak amplitudes were reduced by 20–32% at 0.5 mM [32]. APs recorded ivntracely simple animals with conllularly from rat DRG neurons having Aα/β myelinated primary-afferent fibers also exhibited the sequence of ethylmorphine > codeine ≥ morphine (IC50 = 0.70, 2.5 and 2.9 mM, resperved AP mechanisms,ctively) in AP peak amplitude reduction; this inhibition was resistant to naloxone (0.01 mM) s[67]. Althoucgh as insects, reptiles, squids, or frogs (for examplemany drugs including narcotics, antiepileptics, local anesthetics, alcohols and barbiturates block AP conduction in peripheral nerve fibers, suggesting a nonspecific interaction of the drugs with membrane bilayers [68], the chemical strefer toucture-specific CAP inhibition produced by opioids indicates that opioids act on proteins such as voltage-gated Na+ and K+ channels (see [2369] for review).
AP Morphine is reported to suppress peak Na+ currents and steady-state K+ currents in single flowing on the smyelinated nerve fibers isolated from the frog sciatic nerve, leading to the prolongation of APs [70]. Intracellularface of ly-applied morphine reduced voltage-gated Na+ and K+ channel currve tent amplitudes in squid giant axons [71]. Bath-applied morphine reduced TTX-sensitive Na+ channkel consistingurrent amplitude in DRG neuroblastoma hybridoma cell line ND7/23 cells with an IC50 value of 0.378 mM [56], although Nav1.2 channy fibeels expressed in HEK293 cells were unaffected by morphine at 1 mM [57]. In support of s can be measured as a compound uch an idea about ion channel inhibition, it has been reported that an opioid meperidine, which is used for AP conduction blockade and thus analgesia, inhibits Na+-channels in a manner similar tiono that of lidocaine p[72]. Table 1 summarizes IC50 values for frog sciatential (CAP) by immersing the ic nerve fast-conducting CAP inhibitions produced by opioids together with those for rat sciatic nerve in aCAPs and voltage-gated Na+ channels.
Table 1. Comparison of IC50 values in inhibiting frog or rat sciatic nerve fast-conducting CAPs and TTX-sensitive Na+ channels among opioids.

Opioids

Frog CAP

Rat CAP

TTX-Sensitive

References

 

IC50 (mM)

IC50 (mM)

Na+ Channel Current

 
   

IC50 (mM)

 

Tramadol

2.3

37% reduction

0.194

[49][51][56]

  

(4 mM)

0.103

[57]

Mono-O-desmethyl

-tramadol

9% reduction

  

[49]

(5 mM)

   

Morphine

15% reduction

 

0.378

[56][60]

 

(5 mM)

   

Codeine

30% reduction

  

[60]

 

(5 mM)

   

Ethylmorphine

4.6

  

[60]

Here, where IC50 values are not available, it is partly shown for comparison how CAP amplitudes are reduced by drugs, where % value indicates the extent of the reduction at the concentration shown in parentheses. In clinisolator such as air, oil, or sucrosecal practice, although administration of opioids into the nerve sheath results in pain relief (for instance, see [73]), mand then by putting two electrodes oy of pain treatments by use of opioids are due to systemic administration of centrally-penetrating opioids, leading to their actions in the nerve. CAPs, PNS and CNS, both of which acontribute to analgesia (see [74] for review). sensitive to tetrodotoxIt is possible that centrally-administrated opioids act on not only the CNS but also the PNS, because opioids are reported to be transported to the periphery from brain by P-glycoprotein (TTX),[75]. In support of an importhat blocks voant role of opioids in the PNS, subcutaneous administration of N-methyl-morphine, which did notage-dependen pass through the blood brain barrier, resulted in antinociception in an acetic acid-writhing model in mice [26]. It hasodium channels, and are fast- been reported that a subcutaneously-administrated opioid loperamide, which cannot penetrate into the brain, exhibited an antinociceptive effect in the formalin test in rats [25]. Sucoh anducting (possibly action of opioids in the PNS appeared to be mediated by opioid receptors in peripheral terminals of primary-afferent fibers ([24][25][26][27][76]; see [28] for review). In addition, thick myelinatee inhibitory effect of opioids on nerve AP conduction also might contribute to local analgesia following the peripheral perineural administration of opioids (for instance, see [77]) that are expected to lead to a direct Aα fibers), can be eaaction of opioids at high doses on peripheral nerves. Since codeine is metabolized to morphine via O-demethylation in humans and anilymals ([78][79]; obseee [74] for reved in the sciaiew), peripherally-administrated codeine might have a similar effect to that of morphine.

2.2. NSAIDs

Antinoc nerve trunk isolatediception produced by NSAIDs is mediated by various mechanisms such as (1) inhibition of the synthesis of prostaglandins from frogs by arachidonic acid by inhibiting the cyclooxygenase enzyme ([80][81]; seexp [82][83][84] for reviewsing the), (2) inhibition of acid-sensitive ion channels [85] and transierve trunknt receptor potential (TRP) channels [86][87], (3) acto aivation of several K+ channels ([88][89][90][91][92]; see [93][94] for revirews), (know4) substance P depletion [95], (5) asn interaction with the air-gdrenergic system [96] apnd (6) an methinvolvement of opioids [97][98] and endocannabinoids (see [99] for review). AThe half-peak duration of the CAP was increasidea about an involvement of mechanisms other than cyclooxygenase inhibition in antinociception is supported by a voltage-dependethe observation that there is a dissociation between anti-inflammation and antinociception produced by NSAIDs [100]. An acet delayed rectifier potassiic acid-based NSAID diclofenac reduced frog sciatic nerve CAP peak amplitudes in a partially reversible manner. Diclofenac activity was concentration-dependent in a range of 0.01–1 mM with an IC50 value of 0.94 m channel M. Another acetic acid-based NSAID aceclofenac (a carboxymethyl ester of diclofenac) also exhibited a similar CAP inhibitor, tetraethylammonium, withy action. CAP peak amplitudes were concentration-dependently reduced by aceclofenac in a range of 0.01–1 mM with an IC50 of 0.47 mM, a valut any alteration in itse smaller than that of diclofenac. Other acetic acid-based NSAIDs had an efficacy smaller than those of diclofenac and aceclofenac. Indomethacin at 1 mM reduced CAP peak amplitude, which ines by 38% and acemetacin (where the -OH group of indomethacin is substituted by -OCH2COOH) at 0.5 mM did so by 38%. Etodolacated that potassium channel at 1 mM reduced CAP peak amplitudes by only 15%, and sulindac and felbinac at 1 mM had no effects on CAP peak amplitudes [101]. A similar fre involved in CAPog sciatic nerve CAP inhibition was productionced by fenamic acid-based NSAIDs (tolfenamic acid, meclofenamic [24].acid, mefenamic acid and Aflthough the frog sciatic nerve exhibits both ufenamic acid) whose chemical structures are similar to those of diclofenac and aceclofenac. Tolfenamic acid concentration-dependently reduced CAP peak amplitudes in a range of 0.01–0.2 mM with an IC50 value of 0.29 mM. The ast-conducting and slow-conducting (Aδ-fiber and ctivity of meclofenamic acid (where the chloro group bound to the benzene ring of tolfenamic acid is changed in number and position) was concentration-dependent in a range of 0.01–0.5 mM with an IC-50 value ofib 0.19 mM. Moreover mediated) CAPs, the latter CAPs have much smaller, mefenamic acid (where the chloro group bound to the benzene ring of tolfenamic acid is replaced by methyl group) concentration-dependently reduced CAP peak amplitudes in a range of 0.01–0.2 mM with the extent of 16% at 0.2 mM. CAP peak amplitudes and conduction velocitieswere concentration-dependently reduced by 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) withan an IC50 of 0.22 mM, a value comparable to the former onesose of tolfenamic acid and meclofenamic acid [25101].
Fast 2,6-Diconduhlorodiphenylamine and N-phenylanthranilic acid (whicth are similar ing CAPs recorded from the chemical structure to diclofenac and tolfenamic acid while being not NSAIDs) reduced frog sciatic nerve were found t CAP peak amplitudes; the former compound lacks the -CH2COOH group be inhibited by antinociceptive drugs in a mof diclofenac and the latter one lacks chloro and methyl groups bound to the benzene ring of tolfenamic acid. 2,6-Dichloro- diphenylamine activity was concentration-dependent in a range of 0.001-0.1 mM with the extent of 45% at 0.1 mM; N-phenylanthraner ilic acid activity was concentration-dependent on tin a range of 0.01–2 mM with the extent of 23% at 1 mM [101]. With respect to other types of NSAIDs, salir concentrations and chemical struccylic acid-based (aspirin; 1 mM), propionic acid-based (ketoprofen, naproxen, ibuprofen, loxoprofen and flurbiprofen; each 1 mM) and enolic acid-based [meloxicam (0.5 mM) and piroxicam (1 mM)] NSAIDs had no effects on frog sciatic nerve CAP amplitudes [101]. CAP amplitude res. Amongductions produced by the NSAIDs would be mediated by an inhibition of TTX-sensitive voltage-gated Na+ channels the drugs, there are at are involved in frog CAP production. In support of this idea, diclofenac decreased the peak amplitudes of TTX-sensitive Na+-channeli currents in rat DRG [102] and mouse trically usgeminal ganglion neurons [103]. A similar diclofenac-ind uced Na+-channel inhibitinoon has been reported in rat myoblasts [104] and ventricular cardiceptomyocytes [105]. Flufenamic acid as well as divclofe drugs inac decreased Na+-channel cluding NSAIDurrent amplitudes in rat hippocampal CA1 neurons [26106][107][108],. Although IC50 value (0.22 mM) for flufenany types of mic acid in frog sciatic nerve CAP inhibition was similar to that of Na+ channel inhibition (0.189 mM) in rat hippocampal CA1 neurons [108], IC50 value (0.94 mM) for dicloids such as tramadolfenac in CAP inhibition was much larger than those (0.00851 and 0.014 mM in rat myoblasts and DRG neurons, respectively) of Na+ channel inhibition [27102][28104],. many amide- and ester-type local aneRegarding rank order among NSAIDs, the order for CAP inhibition at 0.5 mM was flufenamic acid > diclofenac > indomethacin >> aspirin = naproxen = ibuprofen [101]; this was in parthe similar to those for Na+ channel inhibition in rat cardiomyocytes (diclofenac > naproxen ≥ ibuprofen; [29105],) antiepilepticsd also in rat DRG neurons (diclofenac > flufenamic acid > indomethacin > aspirin; [30102],). antidepressantWith respect to TTX-resistant Na+ channels [31], diclofexmedetomidinenac at 0.3 mM reduced peak current amplitudes by about 20% in rat trigeminal ganglion neurons (DEX[109]; (+)-(S)-4-[Nav1-(2,3-.8 channel currents were inhibitedimethylphenyl by flufenamic acid and tolfenamic acid (current amplitude reduction: ca. 30 and 30%, respectively, at 0.1 mM; [110]). TTX-ethyl]-1H-imidazole, whsensitive Nav1.7 channel currents were more sensitive to flufenamic acid and tolfenamic acid (reduction: ca. 60 and 70%, respectively, at 0.1 mM) than Nav1.8 ones [110]. Alternatively, ch is an α2-emical irritation-induced activity increase of cadt corenoceptor agonist;neal sensory nerve fibers was suppressed in extent by NSAIDs; this suppression was different in magnitude among distinct types of NSAIDs [32103][111]),. Na+-channel inhibition prod diverse kinds of antinocicepuced by NSAIDs appeared to be different in extent among preparations. Concentrations required for NSAIDs to have a significant inhibitory effect on frog sciatic nerve CAPs were in general higher than those needed to inhibit Na+ channels; this may be attrive compounds isolated from plbuted to various reasons including the fact that not only Na+ channels buts also [33].K+ Tchis entry will describeannels are involved in determining CAP amplitudes. To my knowledge, the effects of antinocicececlofenac, indomethacin, etodolac, acemetacin, meclofenamic acid and mefenamic acid on voltage-gated Na+ channels have not been reported. Table 2 summarizes IC50 value drugs on CAPs evoked s for frog sciatic nerve fast-conducting CAP inhibitions produced by NSAIDs together with those for voltage-gated Na+ channels.
Table 2. Comparison of IC50 values in inhibiting frog sciatic nerve fast-conducting CAPs, TTX-sensitive or -resistant Na+ channels among NSAIDs.

NSAIDs

Frog CAP

IC50 (mM)

TTX-Sensitive

Na+ Channel

Current IC50 (mM)

TTX-Resistant

Na+ Channel

Current IC50 (mM)

References

Acetic Acid-Based

Diclofenac

0.94

0.00851, 0.014

ca. 20% reduction

(0.3 mM)

[101][102][104][109]

Aceclofenac

0.47

  

[101]

Indomethacin

38% reduction (1 mM)

  

[101]

Acemetacin

38% reduction (0.5 mM)

  

[101]

Etodolac

15% reduction (1 mM)

  

[101]

Sulindac

n.d.

(no effect, 1 mM)

  

[101]

Felbinac

n.d.

(no effect, 1 mM)

  

[101]

Fenamic Acid-Based

Tolfenamic acid

0.29

ca. 70% reduction (0.1 mM)

ca. 30% reduction (0.1 mM)

[101][110]

Meclofenamic acid

0.19

  

[101]

Mefenamic acid

16% reduction (0.2 mM)

  

[101]

Flufenamic acid

0.22

ca. 60% reduction

(0.1 mM)

ca. 30% reduction

(0.1 mM)

[101][110]

  

0.189

 

[108]

Salicylic

Acid-Based

Aspirin

n.d.

(no effect, 1 mM)

  

[101]

Propionic

Acid-Based

Ketoprofen

n.d.

(no effect, 1 mM)

  

[101]

Naproxen

n.d.

(no effect, 1 mM)

  

[101]

Ibuprofen

n.d.

(no effect, 1 mM)

  

[101]

Loxoprofen

n.d.

(no effect, 1 mM)

  

[101]

Flurbiprofen

n.d.

(no effect, 1 mM)

  

[101]

Enolic

Acid-Based

Meloxicam

n.d.

(no effect, 0.5 mM)

  

[101]

Piroxicam

n.d.

(no effect, 1 mM)

  

[101]

Here, when IC50 values are not available, it is partly shown for comparison how the CAPs and channels are affected by drugs, where % value indicates the extent of the reduction at the concentration shown in parentheses; n.d.: not determined. NSAIDs (diclofen the ac, aceclofenac, tolfenamic acid, meclofenamic acid and flufenamic acid), which are more effective in frog sciatic nerve CAP inhibition compared to the other NSAIDs [101], have twof benzene frogs and argue how nerve APrings that bind a hydrophilic substituent group, both of which rings are linked by -NH- (see Figures 1Aa, 1Ba, 3Aa, 3Ba, 3Da in [101] for the chemical structures onduction inhibitionsf the five NSAIDs), as seen in local anesthetics. Mefenamic acid (where one of the two benzene rings has a hydrophobic substituent group; see Figure 3Ca in [101]) aproduced by drugs diffpeared to be less effective, albeit not examined at a higher concentration due to a less solubility of this drug (see above). CAPs were effectively inhibited by 2,6-dichlorodiphenylamine and N-phenylanthr among tanilic acid that are not NSAIDs while being similar in chemical structure to NSAIDs having two benzene rings (see Figures 4Aa and 4Ba in [101]). CAPs were also depressed by bisphem.nol A that have For cotwo benzene rings that bind a hydrophilic group such as -OH [112]. Much evidence demponstrates tharison, the effects oft the other actions of NSAIDs depend on their chemical structures. For instance, an involvement of NO-cGMP-K+ channels in antinociceptivon mediate drugd by NSAIDs was dependent on their chemical structures [91][113]. Nonselective on peripheral nerve CAPs in mammals and vcation channels in the rat exocrine pancreas were suppressed by flufenamic acid and mefenamic acid but not indomethacin, aspirin and ibuprofen [114]. There was a distinction in depressing TRP meltage-deastatin-3 channels between diclofenac and aceclofenac [87]. Although NSAIDs not only supprendent sodium andss but also activate TRP ankyrin-1 channels, this activation also differed in magnitude among NSAIDs [115]. pMoreotassium channels that arver, there was a distinction among NSAIDs in the activities of mitochondrial oxidative phosphorylation or electron transport system that may be involved in prtheir adverse side effects [116]. Althoducing APs will also be mgh the concentrations of NSAIDs tested in the frog sciatic nerve are generally much higher than those for voltage-gated Na+-channel intioned, provided that data are availablehibition, such high concentrations are likely when NSAIDs are used at high concentrations in the direct vicinity of nerve fibers. At least a part of analgesia caused by NSAIDs used as a dermatological drug for antinociception may be due to a nerve conduction inhibition through their inhibitory action on voltage-gated Na+ channels [117].

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