Meperidine exerts agonist activity at the α2B-adrenoceptor subtype

Background: The opioid agonist meperidine has actions, such as antishivering, that are more pronounced than those of other opioid agonists and that are not blocked with nonselective opioid antagonists. Agonists at the a. adrenoceptors, such as clonidine, are very effective antishivering drugs. Preliminary evidence also indicates that meperidine interacts with alpha(2) adrenoceptors. The authors therefore studied the ability of meperidine to bind and activate each of the alpha(2)-adrenoceptor subtypes in a transfected cell system. Methods: The ability of meperidine to bind to and inhibit forskolin-stimulated cyclic adenosine monophosphate formation as mediated by the three alpha(2)-adrenoceptor subtypes transiently transfected into COS-7 cells has been tested. The ability of the opioid antagonist naloxone and the alpha(2)-adrerioceptor antagonists yohimbine and RX821002 to block the analgesic action of meperidine in the hot-plate test was also assessed. The ability of meperidine to fit into the alpha(2B) adrenoceptor was assessed using molecular modeling techniques. Results: Meperidine bound to all alpha(2)-adrenoceptor subtypes, with alpha(2B) having the highest affinity (alpha(2B), 8.6 +/- 0.3 muM; alpha(2C), 13.6 +/- 1.5 muM, P < 0.05; alpha(2A), 38.6 +/- 0.7 muM). Morphine was ineffective at binding to any of the receptor subtypes. Meperidine inhibited the production of forskolin-stimulated cyclic adenosine monophosphate mediated by all receptor subtypes but was most effective at the alpha(2B) adrenoceptor (alpha(2B), 0.6 muM; alpha(2A), 1.3 mM; alpha(2C), 0.3 mM), reaching die same level of inhibition (approximately 70%) as achieved with the alpha(2)-adrenoceptor agonist dexmedetomidine. The analgesic action of meperidine was blocked by naloxone but not by the alpha(2)-adrenoceptor antagonists yohimbine and RX821002. The modeling studies demonstrated that meperidine can fit into the alpha(2B)-adrenoceptor subtype. Conclusion: Meperidine is a potent agonist at the alpha(2) adrenoceptors at its clinically relevant concentrations, especially at the alpha(2B)-adrenoceptor subtype. Activation of the alpha(2B) receptor does not contribute significantly to the analgesic action of meperidine. This raises the possibility that some of its actions, such as antishivering, are transduced by this mechanism.