Neuropathic Pain Dysregulates Gene Expression of the Forebrain Opioid and Dopamine Systems

Abstract

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.

Angiotensin receptors and neuropathic pain

“… 63 , 127 In addition, NP conditions are associated with dysregulation of dopaminergic signaling. 133 To the best of our knowledge, a direct connection between dopaminergic disruption and the cerebral RAS has not been established in the context of NP. However, dopaminergic deficiency observed in the early stages of Parkinson disease has been associated with induction of neuroinflammation by activation of glial RAS.…”

Serotonergic Neurotransmission System Modulator, Vortioxetine, and Dopaminergic D2/D3 Receptor Agonist, Ropinirole, Attenuate Fibromyalgia-Like Symptoms in Mice

“…Additionally, a disruption of presynaptic dopaminergic neurotransmission in those brain regions where dopamine plays a putative role in analgesia was shown in FM patients [ 45 ]. Recent human and animal studies have revealed that a decreased level of dopamine or the hypofunction of the dopaminergic system might lead to a significantly lowered pain threshold [ 46 , 47 ] and chronic pain intensification [ 48 ]. In patients suffering from FM, abnormal dopamine function may be associated with differential processing of pain perception [ 49 , 50 ].…”

Painful stimulation increases spontaneous blink rate in healthy subjects

“…One hypothesis is that the relationship between central dopaminergic activity and SBR modulation is due to the activation of antinociceptive mechanisms. Dopamine has been shown to play a critical role in antinociceptive processes 18,19 . Both animal and human studies have indicated that dopamine neurons are activated by acute nociceptive stimuli [48][49][50] and that dopaminergic response is altered during chronic pain 51 .…”

“…Conversely, increased SBR has been observed in conditions characterized by increased dopaminergic tone, such as schizophrenia 14 . Increasing evidence indicates a possible relationship between the central dopaminergic system and pain modulation in both animal and human studies [15][16][17][18][19] . A subpopulation of dopaminergic neurons within the ventrolateral periaqueductal grey (PAG), a brain area included in the descending pain modulatory system 20 , projects to brain regions known to be involved in pain modulation [21][22][23][24] .…”