Disturbances in the function of the mesostriatal dopamine system may contribute to the development and maintenance of chronic pain, including its sensory and emotional/cognitive aspects. In the present study, we assessed the influence of chronic constriction injury (CCI) of the sciatic nerve on the expression of genes coding for dopamine and opioid receptors as well as opioid propeptides in the mouse mesostriatal system, particularly in the nucleus accumbens. We demonstrated bilateral increases in mRNA levels of the dopamine D1 and D2 receptors (the latter accompanied by elevated protein level), opioid propeptides proenkephalin and prodynorphin, as well as delta and kappa (but not mu) opioid receptors in the nucleus accumbens at 7 to 14 days after CCI. These results show that CCI-induced neuropathic pain is accompanied by a major transcriptional dysregulation of molecules involved in dopaminergic and opioidergic signaling in the striatum/nucleus accumbens. Possible functional consequences of these changes include opposite effects of upregulated enkephalin/delta opioid receptor signaling vs. dynorphin/kappa opioid receptor signaling, with the former most likely having an analgesic effect and the latter exacerbating pain and contributing to pain-related negative emotional states.

Chronic pain develops most often from acute pain states elicited by tissue or nerve damage and is most likely underlain by maladaptive plastic changes in the central nervous system produced in response to prolonged nociceptive stimulation. Whereas a large number of pain-related molecular alterations have been described in the spinal cord, a considerable body of evidence now suggests that chronic pain is accompanied by an attenuation of dopaminergic neurotransmission in the mesostriatal pathway, as indicated by reductions of basal extracellular striatal dopamine levels, dopaminergic cell firing, and dopaminergic responses to both noxious and rewarding stimuli.

Strongly suggests that neural processes mediated by both dopamine and opioid systems within the striatum/NAc play important roles in the regulation of descending systems for nociception control as well as in the affective response to the experience of chronic pain. Knowledge of the molecular alterations occurring in these systems during chronic pain, and neuropathic pain in particular, which is scarce at present, seems crucial to understanding their likely contribution to the development and maintenance of neuropathic pain conditions. Thus, we undertook the present study with the aim of providing a comprehensive profile of gene expression changes that occur in the NAc and dorsal striatum in a mouse model of neuropathic pain, considering a set of genes relevant to dopaminergic and opioidergic signaling within these forebrain regions. We demonstrate that strikingly many of these genes are upregulated in the NAc as a result of painful neuropathy. PENK and DOP receptor vs. PDYN and KOP receptor, in neuropathy induced by sciatic nerve injury, may exert opposite influence on pain perception. Increased activity of the PENK/DOP (and MOP) receptor system within the NAc and/or pallidum is likely to suppress pain to some extent but it is apparently dominated by the enhanced PDYN/KOP receptor signaling in the NAc, which probably exacerbates chronic pain and promotes the associated dysphoric emotional disturbances. Thus, we suggest that a disturbed balance between endogenous opioid systems in favor of the pronociceptive one may contribute to the development of mechanical and thermal hypersensitivity in the CCI model of neuropathy.

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