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1. Introduction

Neuropathic pain is a health problem that has negative impacts on both the individual quality of life and the community ^[8][3]. It is associated with significant societal costs resulting from greater healthcare utilization, disability, and loss of productivity ^[9][10][4,5]. Patients with poorly controlled neuropathic pain have significantly poorer health status and increased symptoms of anxiety and depression ^[9][10][4,5]. The mechanisms of neuropathic pain are complex, rendering it a challenge for clinicians to treat effectively ^[11][12][13][13,14,15]. Tricyclic antidepressants (e.g., nortriptyline, desipramine), serotonin–noradrenaline reuptake inhibitors (e.g., duloxetine), and anticonvulsants (e.g., gabapentin, pregabalin) are currently used as first-line treatments for neuropathic pain; however, many patients report incomplete relief of pain as well as adverse effects of these drugs such as cardiotoxicity, dry mouth, orthostatic hypotension, constipation, and dizziness ^[11][12][13,14]. Topical lidocaine (which only acts locally) and opioids (e.g., morphine) are considered as second- and third-line drugs for treatment of neuropathic pain. Opioids have adverse effects including sedation, constipation, physical dependence, respiratory depression tolerance, and addiction ^[11][12][14][13,14,16], and they have a high degree of abuse potential ^[15][17]. The management of neuropathic pain with these contemporary pharmacotherapies exhibits a high failure rate ^[11][12][13][13,14,15]. These treatment failures may occur because of lack of analgesic efficacy, intolerance, contraindications to various classes of medications and the presence of side effects ^{[9][10][11][12][13]}[4,5,13,14,15]. Therefore, a major priority in pain-related research is to identify new therapeutic strategies for treating neuropathic pain. In recent decades, cannabinoid- and endocannabinoid-based therapeutic strategies for neuropathic pain treatment have gained popularity ^{[16][17][18][19][20][21]}[18,19,20,21,22,23].

2. The Effectiveness of Cannabinoids in Chronic Pain Treatment

Various studies have reported that natural and synthetic cannabinoids are effective in the attenuation of acute and chronic pain including neuropathic pain ^{[21][22][23][24][25]}[23,53,54,55,56]. However, the major drawback of using cannabinoids for pain relief is their side effects (cannabimimetic side effects), including sedation, catalepsy (the body becomes stiff), hypothermia, addiction, hypo-locomotion or motor impairment, cognitive impairment and psychological problems ^[26][27][28][57,58,59]. These cannabimimetic side effects are thought to arise mainly because of global activation of the widespread distribution of CB1 receptors in the brain ^{[26][27][28][29]}[57,58,59,60].

To overcome this problem, several alternative strategies have been developed. One strategy is to target CB1 receptors localized in the peripheral tissues ^{[30][31][32][33]}[61,62,63,64]. CB1 agonists with limited or no ability to pass the blood–brain barrier have been developed for this purpose and tested in preclinical animal models ^[32][33][63,64]. Another strategy is to selectively target CB2 receptors because they are predominantly expressed outside of the brain. Studies have reported that CB2 receptor agonists attenuated inflammatory and neuropathic pain ^[34][35][65,66]. Another promising alternative strategy for achieving analgesia is to target endocannabinoids ^{[17][18][36][37][38]}[19,20,67,68,69]. In certain disorders, including neuropathic and inflammatory pain, convincing evidence exists regarding increases in endocannabinoids in certain body regions ^{[17][18][19][36][37]}[19,20,21,67,68]. Exaggerated neuronal activity developed under neuropathic pain conditions may increase the synthesis of endocannabinoids at certain locations of the pain pathway ^[19][39][21,70]. This increase in endocannabinoids may be caused by the body’s autoprotective/defense mechanism; however, the rapid cellular uptake and subsequent degradation of endocannabinoids tends to limit the level of analgesia achieved by endocannabinoids ^{[19][30][37][38]}[21,61,68,69]. Reducing the degradation of endocannabinoids by inhibiting their degrading enzymes can elevate their levels at sites where their actions are pertinent and produce analgesia ^{[19][30][37][38]}[21,61,68,69]. This strategy of increasing endocannabinoids has the benefit of activation of cannabinoid receptors at sites of pain pathways with high endocannabinoid turnover, rather than global activation of CB1 receptors, which can result in side effects ^{[19][30][37][38]}[21,61,68,69].

Analgesic effects of various natural and synthetic cannabinoids for neuropathic pain have widely described and reviewed ^{[16][18][21][22][23]}[18,20,23,53,54]. The presence of cannabimimetic side effects is one of the drawbacks of non-selective cannabinoids due to the widespread distribution of the CB1 receptors in the brain ^[17][18][19,20]. Alternative strategies have developed to overcome this problem by using peripherally acting CB1 receptor agonists, selective CB2 receptor agonists, and endocannabinoid degrading enzyme inhibitors ^[17][18][19][19,20,21]. These strategies are also applicable to NOP.

3. Conclusions

A large number of preclinical studies have provided evidence that targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoid degrading enzymes is a potentially effective strategy to attenuate neuropathic pain symptoms with limited side effects. In particular, enhancing the action of endocannabinoids at the sites of the pain pathway using endocannabinoid degradative enzyme inhibitors is an attractive strategy for the treatment of neuropathic pain. The combination of endocannabinoid degradative enzyme inhibitors with conventional analgesics that have been used for the treatment of neuropathic pain (e.g., opioids) is also a promising strategy to produce synergistic anti-nociceptive effects and to reduce side effects. Studies examining neuropathic pain in the orofacial regions are scarce; therefore, more basic and clinical studies involving NOP are necessary to understand the efficacy and safety of these alternative strategies for neuropathic pain treatment.