Abstract
Tolerance to the pain-relieving effects of cannabinoids limits the therapeutic potential of these drugs in patients with chronic pain. Recent preclinical research with rodents and clinical studies in humans has suggested important differences between males and females in the development of tolerance to cannabinoids. Our previous work found that male mice expressing a desensitization resistant form (S426A/S430A) of the type 1 cannabinoid receptor (CB1R) show delayed tolerance and increased sensitivity to the antinociceptive effects of delta-9-tetrahydrocannabinol (∆9-THC). Sex differences in tolerance have been reported in rodent models with females acquiring tolerance to ∆9-THC faster than males. However, it remains unknown whether the S426A/S430A mutation alters analgesic tolerance to ∆9-THC in mice with chemotherapy-evoked chronic neuropathic pain, and also whether this tolerance might be different between males and females. Male and female S426A/S430A mutant and wild-type littermates were made neuropathic using four once-weekly injections of 5 mg/kg cisplatin and subsequently assessed for tolerance to the anti-allodynic effects of 6 and/or 10 mg/kg ∆9-THC. Females acquired tolerance to the anti-allodynic effects of both 6 and 10 mg/kg ∆9-THC faster than males. In contrast, the S426A/S430A mutation did not alter tolerance to ∆9-THC in either male or female mice. The anti-allodynic effects of ∆9-THC were blocked following pretreatment with the CB1R antagonist, rimonabant, and partially blocked following pretreatment with the CB2R inverse agonist, SR144528. Our results show that disruption of the GRK/β-arrestin-2 pathway of desensitization did not affect sensitivity and/or tolerance to ∆9-THC in a chronic pain model of neuropathy.
Highlights
Chemotherapy-evoked neuropathic pain (CENP) is a doselimiting adverse effect occurring in up to 90% of individuals receiving neurotoxic chemotherapy (Fallon and Colvin, 2013), including the platinum-based cisplatin (Roelofs et al, 1984; Van Der Hoop et al, 1990)
Three-way analysis of variance (ANOVA) indicated that there was a main effect of cisplatin treatment (F1,61 861.6, p < 0.001) indicating that once-weekly treatment with 5 mg/kg of cisplatin caused mechanical allodynia associated with chronic neuropathic pain
The first goal of this study was to determine whether blocking the G protein-coupled receptor kinase (GRK)/β-arrestin-2 pathway of desensitization using the S426A/ S430A mutant mice altered sensitivity and/or tolerance to Δ9THC in a clinically relevant model of chronic pain
Summary
Chemotherapy-evoked neuropathic pain (CENP) is a doselimiting adverse effect occurring in up to 90% of individuals receiving neurotoxic chemotherapy (Fallon and Colvin, 2013), including the platinum-based cisplatin (Roelofs et al, 1984; Van Der Hoop et al, 1990). As cisplatin does not cross the bloodbrain barrier, cisplatin primarily damages peripheral tissuesincluding dorsal root ganglia and sensory fibers (Gregg et al, 1992), resulting in the development of peripheral neuropathy. While treatment options for CENP range from anticonvulsants, antidepressants, and topical treatment, including lidocaine and capsaicin, opioids remain the treatment gold standard (for a review, see Fallon and Colvin, 2013). Opioids display limited efficacy in the context of neuropathic pain (Arnér and Meyerson, 1988; Dellemijn, 1999) while retaining significant abuse liability
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