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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.

SUBMITTER: Wawrzczak-Bargiela A

PROVIDER: S-EPMC7085470 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Wawrzczak-Bargieła Agnieszka A Ziółkowska Barbara B Piotrowska Anna A Starnowska-Sokół Joanna J Rojewska Ewelina E Mika Joanna J Przewłocka Barbara B Przewłocki Ryszard R

Neurotoxicity research 20200205 4

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 ...[more]

PMID: 32026358

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Project description:Deep brain stimulation (DBS) of the medial forebrain bundle (mfb) demonstrated anti-depressant effects both clinically and experimentally. Modulation of mesocorticolimbic dopaminergic (DA) activity could contribute-in part-to the therapeutic effects. By comparing selective and pathway specific midbrain DA optogenetic stimulation with the global, non-pathway specific mfb-DBS, the study explored changes in gene-expression of key biomarkers associated with neurocircuitry of depression. Rats received either optogenetic DAergic or mfb-DBS, delivered as acute/single or chronic/repeated stimulation. Micro-dissected regions were prepared for in situ hybridization targeting biomarkers of GABAergic, glutamatergic, and dopaminergic systems. Mfb-DBS mediated DA independent pathway increased GABAergic biomarkers (GABAA, GAD1) in frontal and accumbal regions, not in midbrain. The combinations of low frequency/high pulse width and high frequency/low pulse width stimulation generally increased biomarker expression similarly, but chronic/repetitive stimulation had no accumulative effect. Interestingly, unilateral stimulation had bilateral effects, but stimulation modalities had little impact on DAT and Vglut2 expression. In conclusion, both low and high frequency, acute/single and chronic/repetitive mfb-DBS-but not selective optogenetic stimulation -activated gene expression of biomarkers associated with GABAergic transmission. The increased expression was transitory and less chronic than predicted. Importantly, the study provides evidence that the anti-depressant therapeutic effects of clinical medial forebrain bundle DBS occurs-in part-be via modulation of GABAergic signalling which in turn could regulate the release of dopamine in frontal and accumbal regions. In addition, clinical implication of the data is that unilateral stimulation had bilateral consequences on the gene expression, although the physiological and functional sequelae of this are yet unknown.

Dataset Information

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

Publications

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

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