The binding of an agonist to MORs usually results in the inhibition of cellular activity; however, there is a growing body of research demonstrating excitatory events downstream to MOR receptor stimulation (9, 10). Both cell culture and animal experiments suggest that opioid-induced analgesia is a consequence of inhibitory cellular effects resulting from the binding of μ-opioid agonists to MOR (11). Since MOR is predominately coupled to Gi, the resulting molecular cascade leads to decreased levels of cAMP (12) and intracellular calcium (13–15) with a resulting inhibition of neuronal activity. The analgesic effect of MOR activation has also been attributed to the release of the Gβγ dimer from Gi/o, which activates inwardly rectifying potassium (GIRK) channels (16) and inhibits voltage-dependent calcium channels (VDCCs) (17). The resulting hyperpolarization suppresses neuronal activity. Adenylyl cyclase inhibition may also contribute to opioid analgesia, since its activation has been suggested to elicit analgesic tolerance or tolerance-associated hyperalgesia (18, 19).
