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Modulation of Ca²⁺ Channels by Heterologously Expressed Wild-Type and Mutant Human µ-Opioid Receptors (hMORs) Containing the A118G Single-Nucleotide Polymorphism

Department of Anesthesiology, Penn State University College of Medicine, Hershey, Pennsylvania

Submitted 22 September 2006; accepted in final form 4 December 2006

The most common single-nucleotide polymorphism (SNP) of the human µ-opioid receptor (hMOR) gene occurs at position 118 (A118G) and results in substitution of asparagine to aspartate at the N-terminus. The purpose of the present study was to compare the pharmacological profile of several opioid agonists to heterologously expressed hMOR and N-type Ca²⁺ channels in sympathetic neurons. cDNA constructs coding for wild-type and mutant hMOR were microinjected in rat superior cervical ganglion neurons and N-type Ca²⁺ channel modulation was investigated using the whole cell variant of the patch-clamp technique. Concentration–response relationships were generated with the following selective MOR agonists: DAMGO, morphine, morphine-6-glucuronide (M-6-G), and endomorphin I. The estimated maximal inhibition for the agonists ranged from 52 to 64% for neurons expressing either hMOR subtype. The rank order of potencies for estimated EC₅₀ values (nM) in cells expressing wild-type hMOR was: DAMGO (31) >> morphine (76) M-6-G (77) endomorphin I (86). On the other hand, the rank order in mutant-expressing neurons was: DAMGO (14) >> morphine (39) >> endomorphin I (74) M-6-G (82), with a twofold leftward shift for both DAMGO and morphine. The DAMGO-mediated Ca²⁺ current inhibition was abolished by the selective MOR blocker, CTAP, and by pertussis toxin pretreatment of neurons expressing either hMOR subtype. These results suggest that the A118G variant MOR exhibits an altered signal transduction pathway and may help explain the variability of responses to opiates observed with carriers of the mutant allele.

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