PRECLINICAL ROLE OF CANNABINOID CB2 RECEPTOR MODULATORS IN THE MANAGEMENT OF NEUROPATHIC PAIN

Neuropathic pain, caused by nerve injury or dysfunction, is a major clinical problem because of the lack of effective treatments and side effects of available therapies. The cannabinoid CB2 receptor, which is highly expressed in immune and peripheral tissues, has an anti-inflammatory and analgesic role. Preclinical evidence emerging illustrates that CB2 receptor modulators, particularly selective agonists, inhibit neuropathic pain behaviors by inhibiting neuroinflammation and nociceptive neuron sensitization with no CNS side effects typical of CB1 receptor activation. This review compiles current progress in CB2 receptor-targeted neuropathic pain pharmacotherapy, detailing mechanisms, efficacy, and prospective therapeutic implications. Neuropathic pain, typically secondary to nerve injury or disease, continues to be a significant clinical problem because of the insufficiency of relief by existing treatments and the weight of their side effects. The cannabinoid CB2 receptor, largely expressed in peripheral tissues and immune cells, becomes significantly increased in both peripheral and central nervous system elements under neuropathic pain conditions. Activation of this receptor by CB2-selective agonists preferentially inhibits sensitized nociceptive neurons and decreases the behavioral expression of pain like mechanical allodynia and thermal hyperalgesia in several animal models, including those involving traumatic nerve injury and chemotherapeutic agents. Mechanistically, modulation of the CB2 receptor blocks neuroinflammatorysignaling, as illustrated by reduced microglial activation and decreased release of pro-inflammatory cytokines, leading to normalization of neuronal excitability and pain thresholds. In contrast to CB1 agonists, CB2-selective compounds are not associated with central nervous system side effects, including psychoactivity and addiction, making them potential candidates for more secure pain therapy. Collectively, preclinical studies emphasize CB2 receptor agonists as significant therapeutic drugs by dampening both peripheral and central sensitization mechanisms in neuropathic pain, which demands further exploration for clinical application. Keywords: Neuropathicpain,CB2agonists, Neuroinflammation, Nociception, hyperalgesia