Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain

BackgroundOpioid management of chronic pain can cause opioid-induced analgesic tolerance and hyperalgesia, complicating clinical pain-management treatments. Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems.MethodsMorphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated-JNK levels, cGMP, and gene expression analysis.ResultsGene expression for the PI3Kγ-AKT-cGMP-JNK signaling pathway including, Akt1, Akt2, Akt3, Pik3cg, Pten, Jnk3, and nNos1 were decreased in the spinal cord with varied expression changes in the dorsal root ganglia and sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We observed significant increases in total and phosphorylated-JNK levels in the spinal cord, total JNK in dorsal root ganglia, and cGMP in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K, nNOS, or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal.ConclusionsOverall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance. Continued research into this pathway will contribute to the development of new analgesic drug therapies.