Chronic Pain, Stress and Endogenous Analgesic Systems

Purpose: Neuropathic pain patients often report severe levels of stress and pain. While acute stress is known to activate endogenous analgesic systems via a phenomenon called stress-induced analgesia, it is unknown how this is affected in a neuropathic pain state. Methods: Restraint stress was used to examine natural activation of endogenous analgesic systems in three groups of C57BL/6 mice. These included mice which underwent CCI of the sciatic nerve to model neuropathic pain, sham operated control mice and unoperated naïve control mice. Results: While naltrexone abolished stress-induced analgesia assessed with the hot-plate, only combined naltrexone and AM281 abolished stress-induced analgesia in the plantar test. Robust stress-induced analgesia was also examined in control sham operated mice which displayed similar pharmacology to control unoperated mice. CCI neuropathic mice, however, displayed severely blunted stress-induced analgesia, which was unaffected by naltrexone or AM281, but was recovered by JZL195. Restraint stress produced neuronal activation within the midbrain PAG and RVM in control sham operated mice but not CCI mice. This was only partly due to reduced serotonergic and increased GABAergic activation of neurons within these brain regions. Conclusions: The findings indicate that the role of endogenous opioids and cannabinoids in stress-induced analgesia varies with the form of analgesia produced. While endogenous cannabinoids do not always have a role in stress-induced analgesia, they can be recruited by reducing their metabolism. In a neuropathic pain state, analgesia induced from restraint stress was reduced; however, this could be partially recovered by blocking endocannabinoid breakdown. Data suggests that the lack of stress-induced analgesia in the neuropathic pain model was due to an inability of higher brain systems to engage the final common pathway of endogenous analgesic system which included the PAG and RVM. These findings indicate that neuropathic pain states disrupt endogenous analgesic systems and that this can be alleviated by targeting the endogenous cannabinoid system representing a novel target for this otherwise intractable pain state