Effects of Cannabinoid Agonists and Antagonists in Rats Discriminating Fentanyl

Extensive evidence suggests the existence of a functional interaction between endogenous cannabinoids and opioid systems. Targeting cannabinoid CB1 receptors might be a promising approach for developing new medications for opioid addiction. The present studies were undertaken to evaluate the effects of CB1 agonists and antagonists in rats (n=8) trained to discriminate, i.p., injections of 0.032 mg/kg fentanyl from saline on a 10-response fixed-ratio (FR-10) schedule of food reinforcement. Results show that the µ-opioid agonists (fentanyl, morphine, and oxycodone) substituted fully for fentanyl, whereas the muscarinic antagonist atropine did not substitute for fentanyl. The CB1 agonists Δ9-THC, AM2201, and AM8936 all partially substituted for fentanyl’s discriminative-stimulus effects suggesting some overlap in the discriminative-stimulus effects of cannabinoid agonists and fentanyl. Pretreatment studies with a µ-opioid receptor antagonist show that naltrexone antagonized fentanyl’s effects. Interestingly, pretreatment studies with CB1 antagonists show that rimonabant (inverse agonist) produced some attenuation of fentanyl’s discriminative-stimulus effects at doses that significantly decreased response rates, whereas the neutral CB1 antagonist AM4113 blocked fentanyl discrimination at doses that did not modify rates of responding. Our findings are consistent with our recent work showing that AM4113 attenuates heroin self-administration in rats, without producing depressive-like effects. Collectively, these data suggests that CB1 neutral antagonists that block CB1 receptors with rimonabant-like potency, devoid of unwanted side-effects, may be therapeutically advantageous for countering the abuse-related behavioral effects of opioids.