MODIFICATION OF FENTANYL’S ANTINOCICEPTIVE, PHYSIOLOGICAL, AND BEHAVIORAL EFFECTS BY CANNABINOID AGONISTS

Abstract

Prescription opioids that are widely used for pain management also produce side effects, including sedation, respiratory depression, constipation, addiction/dependence, and overdose deaths. The absence of similarly effective alternatives suggests that their prominent position in pain management will remain a major public health concern for the foreseeable future. Thus, there is an urgent need for developing non-opioid alternative strategies for the management of pain. Recently, the use of combinations of non-opioid and opioid analgesics has received considerable attention. In this opioid-sparing approach, the combination augments the pain relief provided by the same doses of either drug alone or decreases the need for higher doses thus limiting undesired opioid adverse effects. Mounting evidence suggests the existence of a functional interactions between endogenous cannabinoid (CB) and opioid systems. Given that CB drugs themselves exhibit analgesic properties, targeting the CB system may be a promising approach to overcome the current prescription opioid public health crisis. Indeed, recent studies in human and nonhuman subjects have shown CB1 receptor agonists to enhance the antinociceptive effects of opioids without enhancing their adverse effects. However, none of the utilized CBs yielded a clinically available candidate. The present research is designed to address this important issue by evaluating the effects of novel CB1 agonist that may be useful in combination with prescription opioids. To achieve this goal, the ability of two novel CB1 agonists (AM11101 and AM8936) that vary in efficacy and affinity at CB1 receptors to modify the antinociceptive, respiratory, and behavioral effects of the high efficacy µ-opioid receptor agonist fentanyl were compared to principal psychoactive component of cannabis Δ9-Tetrahydrocannabinol (Δ9-THC). First, the antinociceptive effects of CB1 agonists alone and in combination with fentanyl were determined using a thermal (warm water tail-withdrawal) and chemical (formalin) pain assay. Next, to determine whether doses of CBs that modify fentanyl antinociception affect physiological function, studies were conducted to evaluate the effects of CB1 agonists alone and in combination with fentanyl on respiratory function. Thereafter the effects of fentanyl or CB1 agonist alone and in combination were examined in an open field locomotor activity assay to determine whether doses of CBs that modify fentanyl’s antinociceptive effects cause disruptions in motor behavior. Results demonstrate that the µ-opioid agonist fentanyl and the CB1 agonists Δ9-THC, AM11101, and AM8936 produce a dose-dependent increase in antinociceptive effects in both thermal and chemical pain assays. Pretreatment with CB1 agonists enhanced fentanyl’s antinociceptive effects, as indicated by a significant and dose-dependent leftward shift in the fentanyl dose-response function in both antinociception assays. These results suggest that enhancement of fentanyl’s effects by CB1 agonists consistent across different types of antinociceptive assays. Data from physiological studies confirm that pretreatment with doses of CB1 agonists that enhanced fentanyl antinociception did not modify the respiratory depressant effects of fentanyl. Lastly, locomotor activity data showed that doses of CB1 drugs that enhanced fentanyl antinociception appeared to produce a dose-dependent rightward shift in fentanyl’s dose-response function and delayed the hyperlocomotive effects of fentanyl. Collectively, these data suggest that CB1 agonists can selectively enhance the antinociceptive effects of fentanyl without exacerbating fentanyl’s respiratory depressant and other adverse motor effects. Moreover, compared to full CB1 agonists, utilizing a partial CB1 agonist like AM11101 might be a move viable approach to augment fentanyl’s antinociceptive effects without exacerbating it’s adverse respiratory and behavioral effects. Future work will further evaluate whether doses of CBs that enhance fentanyl’s antinociceptive effects will impact fentanyl’s abuse-related rewarding (e.g., fentanyl-induced conditioned place preference) and neurochemical (e.g., fentanyl-induced DA changes in the brain) effects.