Sex Differences in Anti‐allodynic Tolerance to Δ9‐THC in Desensitization‐resistant S426A/S430A and Wild‐type Mice

Abstract

Tolerance to the anti‐allodynic effects of cannabinoids has the potential to limit their therapeutic potential. A growing body of clinical and preclinical evidence suggests that sex influences a variety of cannabinoid‐related outcomes, including cannabinoid‐induced anti‐allodynia. Male and female mice expressing a desensitization‐resistant form of the cannabinoid type‐1 (CB1) receptor (S426A/S430A) show delayed tolerance to Δ9‐tetrahydrocannabinol (Δ9‐THC) in the tail‐flick assay. Likewise, using the tail‐flick test, male wild‐type mice are more sensitive than females to the anti‐nociceptive effects of Δ9‐THC across the full dose response curve. While the tail‐flick is an acute model of thermal pain, it remains unknown whether these sex‐ and/or genotype differences extend to a chronic model of neuropathic pain. The purpose of the current study was to determine whether the S426A/S430A mutation also alters tolerance to anti‐allodynic effects of Δ9‐THC in a sex‐specific manner. Male and female wild‐type and S426A/S430A mice were assessed for tolerance to the anti‐allodynic effects of 6 and 10 mg/kg of Δ9‐THC in a cisplatin‐evoked model of neuropathic pain. Female mice were less sensitive to the anti‐allodynic effects of 6 mg/kg Δ9‐THC than males. Treatment with 6 mg/kg Δ9‐THC was able to completely reverse allodynia in male, but not female, mice. Female mice showed a complete reversal of allodynia following treatment with 10 mg/kg Δ9‐THC. Interestingly, the S426A/S430A mutation did not alter sensitivity or tolerance development to the anti‐allodynic effects of Δ9‐THC compared to wild‐type mice of either sex, suggesting that the action of Δ9‐ THC at the mutant form of CB1 may be masked by its substantial anti‐allodynic effects through CB2. This study highlights the therapeutic potential of Δ9‐THC in a model of neuropathic pain and suggests that these effects might be mediated in a sex‐specific manner that may have clinical implications for the use of cannabinoids in chronic pain management.Support or Funding InformationNational Institute on Drug Abuse grant DA037355 (DJM); Penn State University College of Medicine Department of Anesthesiology & Perioperative Medicine; Pennsylvania Department of Health using CURE Tobacco Settlement Funds (DJM)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.