Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat

Abstract

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague-Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

Macrophage migration inhibitory factor mediates peripheral nerve injury-induced hypersensitivity by curbing dopaminergic descending inhibition

“… 56 , 57 Direct VTA stimulation may decrease spinal dorsal horn neurons activity to exhibit an analgesic effect. 54 Collectively, the decreased dopamine in the L-SC is largely attributed to decreased dopaminergic projection from VTA in our study. Compared to an enormous number of reports devoted to mesolimbic and mesocortical dopamine pathways in neuropathic pain, 58 , 59 this VTA to L-SC descending dopaminergic pathway in pain regulation after peripheral nerve injury has received scant attention.…”

“… 16 , 51 However, MIF expression in supraspinal regions in response to nerve injury was not evaluated previously, and this study revealed increased MIF expression in the VTA, which is a heterogeneous brain structure in which dopaminergic neurons play distinct roles, not only in rewards and aversive processing, associative learning, general motivational salience and cognition 52 but also in pain regulation. 23 , 53 , 54 Notably, MIF levels were upregulated from 2 to 4 days and peaked at nearly 14–21 days post CCI, and these characteristic changes were coincident with the pain behavior trajectory; further, either i.t. or i.c.v.…”

Manganese-enhanced magnetic resonance imaging depicts brain activity in models of acute and chronic pain: A new window to study experimental spontaneous pain?

“…Our findings are consistent with decreased c-Fos activation in the VTA ( Narita et al, 2003 ) and decreased overall dopamine levels and striatal D2 receptors in an animal model of chronic pain ( Chang et al, 2014 , Taylor et al, 2014 ). Experimental studies support a role of the VTA in the regulation of nociceptive responses ( Li et al, 2016 , Saadé et al, 1997 , Sotres-Bayón et al, 2001 , Takeda et al, 2005 ) and inhibition of dopamine neurones in the VTA encodes negative emotional signals, predicting aversive events in the environment ( Mileykovskiy and Morales, 2011 ). Dopaminergic activation is not likely to occur during chronic pain states ( Baliki and Apkarian, 2015 , Vachon-Presseau et al, 2016 ) and both animal and human studies suggest that hypodopaminergic tone associated with chronic pain impairs motivated behaviour ( Taylor et al, 2016 ).…”

Sustained perturbation in functional connectivity induced by cold pain

“…The role of the VTA in pain is also wellcharacterised. In animals, stimulation of this area increases pain thresholds and decreases spinal dorsal horn activity (Li et al, 2016). In humans, VTA dopaminergic neurons are thought to be responsible for the dopamine release after aversive stimuli, such as psychosocial stress or pain (Taylor et al, 2016).…”