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 synthase through Ca-calmodulin dependent mechanism resulting in increased production of NO (28). In turn, increased levels of NO stimulate guanylyl cyclase, leading to the production of cGMP, activation of PKG, and establishment of a pro-nociceptive phenotype (28). In agreement with this, the newly cloned human 5′-end alternatively spliced isoform of MOR-3 that codes for six transmembrane variant rather than the classic seven transmembrane variant, exhibited a dose-dependent release of NO following treatment with morphine (8). The effect was abrogated by administration of naloxone (8).
