Tonic Suppression of the Mesolimbic Dopaminergic System by Enhanced Corticotropin-Releasing Factor Signaling Within the Bed Nucleus of the Stria Terminalis in Chronic Pain Model Rats

Abstract

Although dysfunction of the mesolimbic dopaminergic system has been implicated in chronic pain, the underlying mechanisms remain to be elucidated. We hypothesized that increased inhibitory inputs to the neuronal pathway from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area (VTA) during chronic pain may induce tonic suppression of the mesolimbic dopaminergic system. To test this hypothesis, male Sprague Dawley rats were subjected to spinal nerve ligation to induce neuropathic pain and then spontaneous IPSCs (sIPSCs) were measured in this neuronal pathway. Whole-cell patch-clamp electrophysiology of brain slices containing the dlBNST revealed that the frequency of sIPSCs significantly increased in VTA-projecting dlBNST neurons 4 weeks after surgery. Next, the role of corticotropin-releasing factor (CRF) signaling within the dlBNST in the increased sIPSCs was examined. CRF increased the frequency of sIPSCs in VTA-projecting dlBNST neurons in sham-operated controls, but not in chronic pain rats. By contrast, NBI27914, a CRF type 1 receptor antagonist, decreased the frequency of sIPSCs in VTA-projecting dlBNST neurons in the chronic pain rats, but not in the control animals. In addition, histological analyses revealed the increased expression of CRF mRNA in the dlBNST. Finally, bilateral injections of NBI27914 into the dlBNST of chronic pain rats activated mesolimbic dopaminergic neurons and induced conditioned place preference. Together, these results suggest that the mesolimbic dopaminergic system is tonically suppressed during chronic pain by enhanced CRF signaling within the dlBNST via increased inhibitory inputs to VTA-projecting dlBNST neurons.

Inhibitory synaptic transmissions to the bed nucleus of the stria terminalis neurons projecting to the ventral tegmental area are enhanced in rats exposed to chronic mild stress

“…The present study revealed that the frequency of sIPSCs in VTA-projecting dlBNST neurons was enhanced in rats exposed to CMS, an animal model of depression, as observed in our previous study using an animal model of chronic pain [8]. Enhanced inhibitory transmission to VTA-projecting dlBNST neurons may be a neuronal mechanism common to depression and chronic pain that causes depression-like behaviors.…”

“…We previously reported that enhanced inhibitory synaptic inputs to VTA-projecting dlBNST neurons observed in the animal model of chronic pain were suppressed by NBI27914, a CRF type I receptor antagonist [8]. However, the current study showed that NBI27914 tended to suppress the CMS-induced facilitation of inhibitory synaptic inputs to VTA-projecting dlBNST neurons, but the effects were not significant, suggesting the different neuroplastic mechanisms for the enhancement of inhibitory synaptic inputs to VTA-projecting dlBNST neurons between CMS and chronic pain.…”

“…1 c). The electrophysiological experiments were performed as described previously [ 8 ]. Briefly, rats were deeply anesthetized with sodium pentobarbital and transcardially perfused with ice-cold cutting solution.…”

“…These findings suggest that suppression of the mesolimbic reward circuit may be a common neuroplastic change underlying depression and chronic pain. Recently, we showed that the mesolimbic dopaminergic system was tonically suppressed during chronic pain by enhanced inhibitory synaptic inputs to neurons projecting from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the VTA [8]. We previously reported that most VTA-projecting BNST neurons are GABAergic neurons that preferentially form synapses on VTA GABAergic neurons [9].…”

Corticotropin-Releasing Factor Neurons in the Bed Nucleus of the Stria Terminalis Differentially Influence Pain Processing and Modulation in Male and Female Mice

“…Elegant work from the Minami group has demonstrated that CRF can be released in the BNST over the course of an hour following formalin injection (Ide et al, 2013), so it is possible that some of the changes we observed over time in our in vivo imaging studies were due to local release of CRF. This is a particularly interesting possibility in the context of chronic pain, since long-term injury has been reported to drive functional upregulations of CRF signaling and putative CRF activity in the BNST (Rouwette et al, 2012;Ide et al, 2013;Takahashi et al, 2019;Hara et al, 2020).…”