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(PTH12) Dopaminergic Deficit in the Anterior Cingulate Cortex in Neuropathic Pain Conditions


Authors:

Kevin Lançon

Edita Navratilova

Philippe Séguéla

Frank Porreca

Maria Zamfir

Abstract:

Background and Aims : The anterior cingulate cortex (ACC) has long been associated with the affective components of pain (Bliss et al., 2016). Pyramidal neurons in layer II/III of the ACC display hyperexcitable characteristics in chronic pain. Reversal/inhibition of this hyperexcitability has proven to provide analgesic benefits. The ACC receives dense dopaminergic inputs from both the ventral tegmental area and substantia nigra. A reduction in dopaminergic input to the mPFC has been linked to chronic pain in Parkinsonian patients however the role of dopamine in the ACC in neuropathic conditions has yet to be investigated. The aim of this study is to examine the effects of increasing both systemically and acutely dopaminergic signaling in the ACC on nociceptive thresholds and development of cortical hyperexcitability in neuropathic models of chronic pain.


Methods : All experiments were performed on 6-week old wild-type C57Bl/6 mice and adult Sprague Dawley rats. The spared-nerve injury (SNI) model for neuropathic pain was used in both species. Whole-cell patch clamp electrophysiology was performed to measure changes in intrinsic excitability of layer 2/3 pyramidal cells in acute brain slices. To increase systemic dopamine levels, L-dopa and carbidopa were provided in the water supply of the mice following SNI. Acute D1 receptor activation in the ACC was performed by microinjection of the D1/5 specific agonist SKF81297. Conditioned place preference (CPP), von Frey assay, and acetone cold tests were used to measure tactile and cold allodynia both in the presence and absence of systemic or acute dopaminergic treatment.


Results : We show that dopamine inhibits pyramidal cells in layer II/III of the ACC via the dopamine D1 receptor (D1R)-dependent activation of hyperpolarization-activated cAMP-gated (HCN) channels. Our results also indicate that increasing systemic dopamine through daily L-dopa/carbidopa uptake both prevents and rescues somatosensory hypersensitivity caused by SNI. Additionally, we demonstrate that systemic increases in dopamine levels prevent the development of SNI-induced pathological cortical hyperexcitability. L-dopa-treated mice who have undergone SNI show a decrease in ACC layer II/III pyramidal cell excitability and input resistance to levels on par with sham mice. Furthermore, our electrophysiology results indicate the L-dopa treatment rescues HCN channel function in the ACC of neuropathic mice. In rats, acute injection of a D1R agonist in rats induced significant conditioned place preference (CPP) specifically in SNI vs. sham animals.


Conclusions : Our results suggest that dopamine is a strong neuromodulator of nociception in chronic pain conditions. Increasing systemic dopaminergic tone reverses both the symptoms and pathological changes of ACC pyramidal cell excitability associated with chronic neuropathic states. Additionally, increasing dopaminergic signaling in the ACC via microinjection of a D1R agonist induced strong CPP, cementing the role of DA in the affective component of pain. L-DOPA therapy is effectively used to treat chronic pain in Parkinsonian patients and our preclinical data indicate it has the potential to alleviate symptoms of neuropathic pain as well.




References : Bliss TV, Collingridge GL, Kaang BK, Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci. 2016
Aug;17(8):485-96.

Conflicts of Interest : None

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