Conversely, the pronociceptive effects of μ-opioid agonists are associated with excitatory cellular events: increase in levels of cAMP (20) and intracellular Ca2+ (21). Excitatory cellular events have been implicated in molecular mechanism of opioid receptor-mediated hyperalgesia, tolerance, and dependence (22). Both extremely low and extremely high doses of morphine, as well as chronic administration of opioids, can elicit a hyperalgesia in both human clinical and animal models of pain (22–24). A dual effect of opioids on cAMP and Ca2+ levels in vitro has been corroborated by Rubovitvh and coworkers (9). It has been proposed that a switch in the G-protein coupling profile of the OPRM1 from Gi to both Gs and Gq as well as adenylyl cyclase (AC) activation by Gβγ explains the phenomenon of opioid induced excitation (9, 25, 26). It has also been established that the activation of cAMP and cGMP cascades through Ca2+-dependent activation of nitric oxide synthase leads to activation of protein kinases A (PKA) and G (PKG) and establishment of a pronociceptive phenotype (27). The increased influx of Ca2+ leads to activation of nitric oxide
