Effects of cannabinoid type 2 receptor agonist on the development of nucleoside reverse transcriptase inhibitor-induced neuropathic pain in mice

Abstract

Neuropathic pain associated with nucleoside reverse transcriptase inhibitors (NRTIs), therapeutic agents for human immunodeficiency virus (HIV), responds poorly to the currently available drugs. Cannabis, which activates cannabinoid type 1 (CB1) and CB2 receptors, has been reported to relieve HIV-associated neuropathic pain in clinical trials. However, the activation of the CB1 receptor is associated with side effects such as psychosis and physical dependence. Therefore, I investigated the antiallodynic effects of β-caryophyllene (BCP), a CB2 selective phytocannabinoid, in a mouse model of NRTI-induced neuropathic pain. Female BALB/c mice treated with 2′-3′- dideoxycytidine (ddC, zalcitabine), a NRTI, for 5 days, developed mechanical allodynia but had no changes in response to thermal stimuli. Administration of ddC increased the expression of mRNA of cytokines (interleukin 1 beta, tumor necrosis factor-alpha, and interferon-gamma), and the phosphorylated level of extracellular signal-regulated kinase p44/42 (ERK1/2). However, the administration of ddC did not alter the phosphorylated level of p38 mitogen-activated protein kinase (p38 MAPK) or the protein levels of the astrocytes and microglia markers: glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1), respectively. In addition, the administration of ddC did not alter the mRNA levels of Gfap but slightly downregulated the mRNA levels of another microglia marker: cluster of differentiation 11b (Cd11b), suggesting a lack of activation of brain microglia and astrocytes. Co-treatment with ddC and BCP, minocycline or pentoxifylline prevented the development of ddC-induced mechanical allodynia. In addition, BCP attenuated the established ddC-induced mechanical allodynia. The CB2 receptor antagonist AM 630, but not the CB1 receptor antagonist AM 251, blocked the antiallodynic effects of BCP. β-caryophyllene prevented the ddCinduced increase in cytokines mRNA, and the phosphorylated level of ERK1/2. In conclusion, BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation. Therefore, BCP could be useful for the prevention and treatment of antiretroviral-induced neuropathic pain.