Behavioral evidence for mu-opioid and 5-HT2A receptor interactions

Electrophysiological studies have demonstrated a physiological interaction between 5-HT2A and mu-opioid receptors in the medial prefrontal cortex. Furthermore, behavioral studies have found that phenethylamine hallucinogens induce head shakes when directly administered into the medial prefrontal cortex. The receptor(s) by which morphine suppresses head shakes induced by serotonin agonists have not been characterized. We administered mu-opioid receptor agonists and antagonists to adult male Sprague-Dawley rats prior to treatment with the phenethylamine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which is known to induce head shakes via 5-HT2A receptors. The suppressant action of the moderately selective mu-opioid receptor agonist, buprenorphine (ID50 approximately 0.005 mg/kg, i.p.; a mu-opioid receptor partial agonist and kappa-opioid receptor antagonist) was blocked by naloxone and pretreatment with the irreversible mu-opioid receptor antagonist clocinnamox. Another mu-opioid receptor agonist fentanyl also suppressed DOI-induced head shakes. In contrast, a delta-opioid receptor agonist was without effect on DOI-induced head shakes. Thus, activation of mu-opioid receptors can suppress head shakes induced by hallucinogenic drugs.