Meperidine Exerts Agonist Activity at the α2B-Adrenoceptor Subtype

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Abstract

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 α2 adrenoceptors, such as clonidine, are very effective antishivering drugs. Preliminary evidence also indicates that meperidine interacts with α2 adrenoceptors. The authors therefore studied the ability of meperidine to bind and activate each of the α2-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 α2-adrenoceptor subtypes transiently transfected into COS-7 cells has been tested. The ability of the opioid antagonist naloxone and the α2-adrenoceptor 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 α2B adrenoceptor was assessed using molecular modeling techniques.

Results

Meperidine bound to all α2-adrenoceptor subtypes, with α2B having the highest affinity (α2B, 8.6 ± 0.3 μm; α2C, 13.6 ± 1.5 μm, P < 0.05; α2A, 38.6 ± 0.7 μm). 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 α2B adrenoceptor (α2B, 0.6 μm; α2A, 1.3 mm; α2C, 0.3 mm), reaching the same level of inhibition (approximately 70%) as achieved with the α2-adrenoceptor agonist dexmedetomidine. The analgesic action of meperidine was blocked by naloxone but not by the α2-adrenoceptor antagonists yohimbine and RX821002. The modeling studies demonstrated that meperidine can fit into the α2B-adrenoceptor subtype.

Conclusion

Meperidine is a potent agonist at the α2 adrenoceptors at its clinically relevant concentrations, especially at the α2B-adrenoceptor subtype. Activation of the α2B 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.

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