We previously reported that sustained enhancement of CRF signaling within the BNST during chronic pain suppresses the dopaminergic neurons in the ventral tegmental area [2]. However, it remains to be examined whether chronic pain alters the neuronal excitability of CRF neurons in the BNST. In this study, we utilized CRF-Cre; Ai14 mice to visualize CRF-expressing neurons in the brain slices prepared from the mouse model of neuropathic pain and examined chronic pain-induced changes in excitability of ovBNSTCRF neurons. The results showed that chronic pain elevated neuronal excitability of ovBNSTCRF neurons.

Alcohol withdrawal, which is known to cause increased anxiety-like behavior [7], has been shown to increase excitability of a subpopulation of putative local CRF-expressing neurons in the BNST [8]. Hu et al. reported that chronic variable mild stress (CVMS) induced anxiety- and depression-like behaviors and increased neuronal excitability of ovBNSTCRF neurons and that intra-ovBNST injection of R121919, a CRFR1-selective antagonist, ameliorated the CVMS-induced anxiety- and depression-like behaviors [9]. These findings suggest that enhanced neuronal excitability of ovBNSTCRF neurons induces anxiety- and depression-like behaviors under the pathological conditions. Hu et al. also reported that increased excitability of ovBNSTCRF neurons was caused by potentiation of miniature excitatory postsynaptic currents and inhibition of M-currents [9]. A similar mechanism may be involved in the enhanced excitability of ovBNSTCRF neurons during neuropathic pain. In addition to the BNST-intrinsic neurons, CRF-expressing central amygdala (CeA) neurons send their axons to the BNST. Asok et al. reported that optogenetic inhibition of a CRF pathway from the CeA to the BNST disrupted sustained fear [10]. Furthermore, Rouwette et al. [11] and our group [2] demonstrated that CRF mRNA expression was elevated both in the BNST and CeA of neuropathic pain model rats. These findings suggest the involvement of not only BNST-intrinsic but also CeA-derived CRF nerve terminals in the enhanced CRF signaling within the BNST during neuropathic pain.

The results of this study, together with our previous studies showing that enhanced CRF signaling in the BNST caused the aversive responses in acute pain [1] and suppressed the brain reward system in chronic pain [2], suggest that chronic pain induces negative emotional states by increasing neuronal excitability of ovBNSTCRF neurons.