Summary: Inhibitory inputs to the neural circuit between the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area (VTA) increase when a person is in chronic pain. This alteration is mediated by enhanced corticotropin-releasing factor signaling within the dlBNST, leading to suppression of the mesolimbic dopaminergic system. The result is depressive mood and anhedonia associated with chronic pain.
Source: Hokkaido University
Researchers at Hokkaido University have identified the brain mechanism linking chronic pain and depression in rats. Their research, which was recently published in The Journal of Neuroscience, could lead to the development of new treatments for chronic pain and depression.
“Clinicians have known for a long time that chronic pain often leads to depression, however the brain mechanism for this was unclear,” said Professor Masabumi Minami at Hokkaido University, one of the authors of the paper.
The researchers looked at how neuronal pathways were affected by chronic pain in rats. They used an electrophysiological technique to measure the activities of neurons after four weeks of chronic pain. They found that persistent pain caused changes in the neuronal pathway projecting from the brain region called bed nucleus of the stria terminalis (BNST) to the region called ventral tegmental area (VTA). Specifically, they found enhanced signaling mediated by corticotropin-releasing factor (CRF), which is a neuropeptide known to be involved in the negative emotions such as anxiety and fear, in the BNST of chronic pain animals. Crucially, they showed that this enhanced CRF signaling leads to suppression of the brain reward system, the nervous system that is activated by rewards and related to production of pleasure and motivation. Suppression of the reward system is considered to be an underlying mechanism of depression, which leads to decreased pleasure and motivation.
“By clarifying the mechanism by which the brain reward system is continuously suppressed, we found the missing link between chronic pain and depression,” says Masabumi Minami.
The researchers found that when they treated the rats with a drug that blocked the excessive CRF signals, the activity of dopamine neurons, which play an important role in the brain reward system, was increased. This suggests that drugs targeting neuropeptides such as CRF could be developed in order to treat chronic pain and depression in the future.
“These findings could not only lead to improved treatment of emotional aspect of chronic pain, but also to new therapeutics for depressive disorders,” says Masabumi Minami.
Funding: This study was supported by a Grant-in-Aid for Scientific Research (B) (23300130, 26290020, 17H03556) and Challenging Research (Exploratory) (17K19469) from the Japan Society for the Promotion of Science (JSPS), a Grant-in-Aid for Scientific Research on Innovative Areas on the “Unraveling the micro-endophenotypes of psychiatric disorders at the molecular, cellular and circuit levels” (25116501, 15H01273) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and the Japan Agency for Medical Research and Development (JP19gm0910012).
About this neuroscience research article
Source: Hokkaido University Media Contacts: Naoki Namba – Hokkaido University Image Source: The image is adapted from the Hokkaido University news release.
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
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 inhibitory postsynaptic currents (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. Taken 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 comorbidity of chronic pain and depression has long been recognized. Although dysfunction of the mesolimbic dopaminergic system has been implicated in both chronic pain and depression, the underlying mechanisms remain to be elucidated. Here we show that the inhibitory inputs to the neuronal pathway from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area increase during chronic pain. This neuroplastic change is mediated by enhanced corticotropin-releasing factor signaling within the dlBNST that leads to tonic suppression of the mesolimbic dopaminergic system, which may be involved in the depressive mood and anhedonia under the chronic pain condition.