Reduced Accumbal Dopamine Efflux Via Orexin OX₂ Receptors in Chronic Pain Models

We have shown using isolated C-fiber-like neurons that chronic pain may reduce orexinergic neural activity and that the nucleus accumbens, a major terminal area of the mesolimbic dopaminergic system, contains OX₂-receptors, a subtype of orexin receptors that inhibits accumbal basal dopamine efflux. It has been suggested that stimulation of OX₂ receptors in the brain may suppress chronic pain. To investigate how chronic pain affects orexin receptor-mediated changes in accumbal dopaminergic neural activity, we analyzed the effects of intra-accumbal infusion of orexin receptor ligands on accumbal dopamine efflux in rats using in vivo microdialysis. To experimentally induce two types of chronic pain, i.e., inflammatory and neuropathic pain, we performed, respectively, intra-plantar injection of the proinflammatory compound carrageenan into the hind paws and sciatic nerve ligation. Decreased paw withdrawal threshold following carrageenan treatment or sciatic nerve ligation was inhibited by morphine. However, meloxicam, a nonsteroidal anti-inflammatory drug, inhibited these changes in carrageenan-treated rats but not in those with sciatic nerve ligation. Neither carrageenan injection nor sciatic nerve ligation altered basal accumbal dopamine efflux. Both in carrageenan-treated and in sciatic nerve-ligated rats, the OX₁- and OX₂-receptor antagonist MK-4305 and OX₂-receptor antagonist EMPA-induced increase in accumbal dopamine efflux was reduced, as compared to their respective controls. The OX₂-receptor agonist orexin-B counteracted the EMPA-induced increase in dopamine efflux both in carrageenan-treated and in sciatic nerve-ligated rats. These results suggest that inflammatory and neuropathic pain each lead to decreased stimulation of accumbal OX₂-receptors by their endogenous agonists, orexin-A and/or orexin-B, thereby inhibiting dopamine efflux.