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.
The comorbidities of depression and chronic pain have long been recognized in the clinic, and several preclinical studies have demonstrated depression-like behaviors in animal models of chronic pain. These findings suggest a common neuronal basis for depression and chronic pain. Recently, we reported 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 ventral tegmental area (VTA), suggesting that tonic suppression of the mesolimbic dopaminergic system by this neuroplastic change may be involved in chronic pain-induced depression-like behaviors. In this study, we hypothesized that inhibitory synaptic inputs to VTA-projecting dlBNST neurons are also enhanced in animal models of depression, thereby suppressing the mesolimbic dopaminergic system. To test this hypothesis, we performed whole-cell patch-clamp electrophysiology using brain slices prepared from rats exposed to chronic mild stress (CMS), a widely used animal model of depression. The results showed a significant enhancement in the frequency of spontaneous inhibitory postsynaptic currents in VTA-projecting dlBNST neurons in the CMS group compared with the no stress group. The findings revealed enhanced inhibitory synaptic inputs to VTA-projecting dlBNST neurons in this rat model of depression, suggesting that this neuroplastic change is a neuronal mechanism common to depression and chronic pain that causes dysfunction of the mesolimbic dopaminergic system, thereby inducing depression-like behaviors.
We previously reported that VTA-projecting dorsolateral bed nucleus of the stria terminalis (dlBNST) neurons make synapses onto the VTA GABAergic neurons, suggesting that suppression of these projecting neurons may lead to activation of VTA GABAergic neurons, thereby suppressing VTA dopaminergic neurons. Recently, using electrophysiological analyses, we found the increased inhibitory inputs to VTA-projecting dlBNST neurons mediated by enhanced CRF signaling in the dlBNST of chronic pain model rats. CRF production has been reported to be produced in both intrinsic neurons within the dlBNST and the neurons projecting from the central amygdala to the dlBNST. Therefore, in this study, CRF mRNA expression in these brain areas of chronic pain model rats was examined by in situ hybridization histochemistry (ISH). CRF mRNA expression was increased in both dlBNST and CeA. In addition, the influence of the enhanced CRF signaling in the dlBNST on VTA dopaminergic neuron activity was examined by ISH and in vivo microdialysis. Injection of CRF type 1 receptor antagonist into the dlBNST of chronic pain model rats increased c-fos mRNA expression in the VTA TH-positive neurons and dopamine release in the nucleus accumbens, indicating the suppression of VTA dopaminergic neuron activity by enhanced CRF signaling in the dlBNST during chronic pain.
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