Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain

Abstract

Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.

Possible Therapeutic Options for Complex Regional Pain Syndrome

“…Such robust expression levels provide evidence that neuropathic pain is modulated through changes in FAAH signaling. Several studies have shown that FAAH inhibition attenuates mechanical and thermal hyperalgesia in CRPS models [ 26 , 28 , 29 ]. In addition, NAPE-PLD, which is synthesized in tissue, elevates anandamide levels.…”

The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man

“…After the discovery of the CB 1 receptors and their important role in pain modulation, the first significant drug discovery program for peripherally restricted CB 1 agonists was analgesics. The concept was to utilize the analgesic effects of CB 1 activation without the CNS side effects, and extensive preclinical studies have demonstrated the analgesic effects of these compounds across various models of pain [126]. However, a lack of efficacy in clinical studies [124,125] meant the pharmaceutical development of these medicines was terminated.…”

Peripherally Acting Opioids in Orofacial Pain

“…Currently, medications for orofacial pain mainly include tricyclic antidepressants, serotonin–noradrenaline reuptake inhibitors, opioids, and non-steroidal anti-inflammatory drugs ( Clark et al, 2016 ). However, these therapeutic agents are often ineffective in relieving pain and are associated with various adverse effects, such as respiratory depression, constipation, cardiotoxicity, and dizziness ( Fornasari, 2017 ; Hossain et al, 2020 ). Undoubtedly, opioids are the most potent drugs for moderate-to-severe pain control ( Wiffen et al, 2017 ), and drugs based on PORs are effective for pain relief without central side effects.…”