Cannabis-derived terpenes as novel neuropathic pain therapeutics: preclinical mouse studies and possible cannabinoid receptor involvement

Jenny Wilkerson
University of Florida

Objective: Anecdotal reports suggest cannabis may be an effective analgesic. Cannabis contains a multitude of compounds (i.e., terpenes) that have not been well studied and may hold therapeutic promise as pain therapeutics. We examined the ability of a subset of terpenes found in cannabis: γ-terpinene, α-terpineol, β-caryophyllene to reverse mechanical allodynia (i.e., light touch sensitivity) in mice experiencing paclitaxel chemotherapy-induced peripheral neuropathy (CIPN) and in the chronic constriction injury of the sciatic nerve (CCI) neuropathic pain model. To examine cannabinoid receptor involvement within both neuropathic pain models we also tested each terpene in mice lacking either functional cannabinoid type 1 receptors (CB1R (-/-)) or cannabinoid type 2 receptors (CB2R (-/-)).

Methods: Male and female wildtype, CB1R (-/-), CB2R (-/-) mice on a C57BL/6J background were used in all experiments. CIPN was induced with one cycle of paclitaxel, consisting of a total of four intraperitoneal injections of paclitaxel (8 mg/kg per injection), and injections are given every other day. Separate cohorts underwent CCI surgery utilizing chromic gut suture to ligate the sciatic nerve. Mechanical allodynia was assessed via von Frey filaments. After the presence of mechanical allodynia was confirmed, mice were injected intraperitoneally (i.p.) with vehicle, α-terpineol (5.6-178 mg/kg) β-caryophyllene (56-320 mg/kg) or γ-terpinene (56-320 mg/kg) and tested.

Results: Each terpene dose-relatedly reversed mechanical allodynia in both models. Higher doses of each terpene were required to achieve maximal reversal in the CIPN model. The rank order potency of the terpenes was α-terpineol > β-caryophyllene > γ-terpinene. Compared to wildtype mice, both CB1R (-/-), CB2R (-/-) mice treated with α-terpineol displayed a significant rightward shift in potency to reverse mechanical allodynia in both models. β-caryophyllene-induced reversal of mechanical allodynia underwent a significant rightward shift in potency in CB2R (-/-) mice in both models. Both CB1R (-/-) and CB2R (-/-) mice treated with γ-terpinene displayed a significant rightward shift in potency to reverse CIPN mechanical allodynia. This contrasts with the CCI model as only CB1R (-/-) mice displayed a rightward shift.

Conclusions: These findings suggest these terpenes may have differential cannabinoid receptor activity. Cannabis-based terpenes may yield novel analgesics.

Co-authors: Yuma Ortiz1, Lane McMahon1
1University of Florida

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