Stimulating GABAergic Neurons in the Nucleus Accumbens Core Alters the Trigeminal Neuropathic Pain Responses in a Rat Model of Infraorbital Nerve Injury.

Jaisan Islam,Elina Kc,Soochong Kim,Young Seok Park,Hyong Kyu Kim

doi:10.3390/ijms22168421

Abstract

The nucleus accumbens core (NAcc) is an important component of brain reward circuitry, but studies have revealed its involvement in pain circuitry also. However, its effect on trigeminal neuralgia (TN) and the mechanism underlying it are yet to be fully understood. Therefore, this study aimed to examine the outcomes of optogenetic stimulation of NAcc GABAergic neurons in an animal model of TN. Animals were allocated into TN, sham, and control groups. TN was generated by infraorbital nerve constriction and the optogenetic virus was injected into the NAcc. In vivo extracellular recordings were acquired from the ventral posteromedial nucleus of the thalamus. Alterations of behavioral responses during stimulation “ON” and “OFF” conditions were evaluated. In vivo microdialysis was performed in the NAcc of TN and sham animals. During optogenetic stimulation, electrophysiological recordings revealed a reduction of both tonic and burst firing activity in TN animals, and significantly improved behavioral responses were observed as well. Microdialysis coupled with liquid chromatography/tandem mass spectrometry analysis revealed significant alterations in extracellular concentration levels of GABA, glutamate, acetylcholine, dopamine, and citrulline in NAcc upon optic stimulation. In fine, our results suggested that NAcc stimulation could modulate the transmission of trigeminal pain signals in the TN animal model.

Highlights

Trigeminal neuralgia (TN) or “tic douloureux” can present as an extreme form of chronic neuropathic pain and include a spontaneous and exaggerated painful response alongside a negative affective, motivational, and cognitive state [1,2]
To analyze the effects of stimulating nucleus accumbens (NAc) core (NAcc) in a TN condition, we used an optogenetic stimulation approach with the human synapsin promoter to increase the activity of GABAergic neurons in NAcc, as it is well-established that pptogenetics is suitable for understanding the functional dissection of neural circuits that manipulate the neural substrates of behavior, as it can achieve more precise temporal and spatial control over specific neural populations than pharmacological or electrical interventions [7,13,14]
Following ION ligation, the behavioral test scores of the air-puff test, cold allodynia score test, and mechanical allodynia test suggested the presence of chronic pain in the TN animals

Summary

Introduction

Trigeminal neuralgia (TN) or “tic douloureux” can present as an extreme form of chronic neuropathic pain and include a spontaneous and exaggerated painful response alongside a negative affective, motivational, and cognitive state [1,2]. The typical form of TN responds satisfactorily to surgical interventions, the atypical form of TN does not [2,3] To overcome this and find an efficacious solution, maladaptive neural circuits linked with different states in the brain have been widely studied. An important aspect of the NAc, where approximately 95% of the neurons are GABAergic medium spiny neurons (MSNs) [4], is often overlooked, which is its significant intervention in pain regulation by modulating its projections of medium spiny neurons to get positive feelings and effects of reward from pain relief [5]. Through its projection to the PAG-RVM and brainstem, NAc may affect behavioral outcomes by manipulating the emotional aspects of pain through the descent of the dopaminergic pathway and GABAergic input to the other brain areas [6,7,8,9,10]. To analyze the effects of stimulating NAcc in a TN condition, we used an optogenetic stimulation approach with the human synapsin promoter to increase the activity of GABAergic neurons in NAcc, as it is well-established that pptogenetics is suitable for understanding the functional dissection of neural circuits that manipulate the neural substrates of behavior, as it can achieve more precise temporal and spatial control over specific neural populations than pharmacological or electrical interventions [7,13,14]

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