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.

Keywords: CB2-selective agonists; endocannabinoid-degrading enzyme inhibitors; neuropathic orofacial pain; neuropathic pain; peripherally restricted CB1 agonists.

Figure 1

A possible mechanism of attenuation of neuropathic pain following infra-orbital nerve injury. 2-AG production in the brainstem trigeminal nucleus caudalis (Vc) may be increased by postsynaptic neurons because of exaggerated presynaptic neuronal activity under neuropathic pain conditions and rapidly degraded by MAGL. Prevention of the rapid degradation of 2-AG by JZL184 (an MAGL inhibitor) may increase its localized accumulation. Localized accumulation of 2-AG can act on CB1 receptors present in the presynaptic neurons and CB2 receptors present in microglia. Activation of CB1 receptors can inhibit voltage-gated Ca²⁺ channels (VGCCs), resulting in reduction of release of excitatory neurotransmitters from presynaptic neurons. Activation of CB2 receptors in microglia can inhibit the release of pro-inflammatory mediators. Reduction of release of excitatory neurotransmitters and pro-inflammatory mediators by accumulated 2-AG may cause attenuation of neuropathic pain symptoms. 2-AG: 2-arachydonoylglycerol; CB1R: cannabinoid 1 receptor; CB2R: cannabinoid 2 receptor; DAG: diacylglycerol; DAGL: diacylglycerol lipase; AA: arachidonic acid; MAGL: monoacylglycerol lipase; Glut.: glutamate; M: microglia.