Cannabinoid Receptor 1 Positive Allosteric Modulator (GAT229) Attenuates Cisplatin-induced Neuropathic Pain in Mice

Chemotherapy-induced peripheral neuropathy (CIPN) is one of chemotherapies' most often documented side effects. Patients with CIPN experience spontaneous burning, numbness, tingling, and neuropathic pain in their feet and hands. Currently, there is no effective pharmacological treatment to prevent or treat CIPN. Activating the cannabinoid receptor type 1 (CB) by orthosteric agonists has shown promising results in alleviating the pain and neuroinflammation associated with CIPN. However, the use of CB orthosteric agonists is linked to undesirable side effects. Unlike the CB orthosteric agonists, CB positive allosteric modulators (PAMs) don't produce any psychoactive effects, tolerance, or dependence. Previous studies have shown that CB PAMs exhibit antinociceptive effects in inflammatory and neuropathic rodent models. This study aimed to investigate the potential benefits of the newly synthesized GAT229, a pure CB PAM, in alleviating neuropathic pain and slowing the progression of CIPN. GAT229 was evaluated in a cisplatin-induced (CIS) mouse model of peripheral neuropathic pain (3 mg/kg/d, 28 d, i.p.). GAT229 attenuated and slowed the progression of thermal hyperalgesia and mechanical allodynia induced by CIS, as evaluated by the hotplate test and von Frey filament test. GAT229 reduced the expression of proinflammatory cytokines in the dorsal root ganglia (DRG) neurons. Furthermore, GAT229 attenuated nerve injuries by normalizing the brain-derived neurotrophic factor and the nerve growth factor mRNA expression levels in the DRG neurons. The CB receptor antagonist/inverse agonist AM251 blocked GAT229-mediated beneficial effects. According to our data, we suggest that CB PAMs might be beneficial in alleviating neuropathic pain and slowing the progression of CIPN.