Josée Guindon of Texas Tech University and Health Sciences Center will present a lecture entitled: Antinociceptive tolerance to CB1 and mixed CB1/CB2 receptor agonists is sex-specific and linked to hormonal changes in the chemotherapy-induced neuropathic pain model.
Abstract: The beneficial effect of chemotherapeutic agents on tumor suppression comes with major unwanted side effects such as chemotherapy-induced neuropathic pain (CIPN). These peripheral sensory and motor deficits are poorly treated by our current analgesics with limited effectiveness and constitute a clinical challenge for cancer patients. The development of novel targeted therapies with long term efficacy in alleviating CIPN is an ongoing focus of preclinical research. The endocannabinoid system has shown great promise and efficacy in alleviating CIPN in both preclinical and clinical studies. Our group and others have shown that CB1 and mixed CB1/CB2 receptor agonists display antinociceptive properties in chronic pain. Recent interest in investigating sex-differences in antinociceptive effects and development of tolerance have changed our former understanding of antinociceptive tolerance solely based on male studies. The objective of our current work is thus to assess whether development of antinociceptive tolerance to CB1 (ACEA) and mixed CB1/CB2 (CP55,940) receptor agonists develop differently in male and female mice in regards to time of occurrence, sex-hormone changes and inflammatory markers. Tolerance to the antinociceptive effect of ACEA and CP55,940 were assessed by mechanical allodynia testing (von Frey) with the development of tolerance appearing after 5 (female) or 9 (male) days for ACEA and after 7 (female) or 11 days (male) for CP55,940 following chronic administration in wild-type mice. We found a decrease in estradiol levels in female and no change in testosterone levels in male when ACEA and CP55,940 were administered chronically. We also observed changes in inflammatory markers in ovaries and testis. These results demonstrate the role played by sex-hormones in the development of antinociceptive tolerance and the potential role in inducing changes in inflammatory markers in sex-specific tissues. Future studies are necessary to confirm the role of sex-hormones in the development of tolerance and their possible involvement in changing inflammatory markers leading to a more complex sex-specific mechanism of cannabinoid tolerance.
Acknowledgements: Funded by NIH grants DA044999-01A1S1 (JG), DA044999-01A1 (JG) and Texas Tech University Health Sciences Center School of Medicine 121035 (JG).