Possible involvement of hypothalamic paraventricular nucleus PACAP in chronic pain-induced negative emotional responses in mice

Recent evidence has suggested that pituitary adenylate cyclase-activating polypeptide (PACAP) has critical roles in central and peripheral pathways, such as spino-parabrachio-amygdaloid and hypothalamic-pituitary-adrenal pathways, mediating stress-related negative emotional behaviors. Although it is well established that there is a great degree of comorbidity of chronic pain and negative emotional behaviors, the cellular mechanism underlying chronic pain and anxiety/depression interaction still remains to be elucidated. Here, we evaluated possible involvement of PACAP signaling in the development of anxiety- and depression-like behaviors after peripheral nerve injury in mice. We observed that spinal nerve ligation (SNL) induced anxiety- and depression-like behaviors lasting for at least 3 weeks in wild-type (PACAP +/+) mice. However, the development of SNL-induced anxiety- and depression-like behaviors was almost completely abrogated in PACAP -/- mice. Furthermore, we found that selective overexpression of PACAP by the infection of adeno-associated virus in the hypothalamic paraventricular nucleus (PVN), but not neighboring ventromedial hypothalamus, region resulted in the induction of anxiety-like behavior. In contrast, siRNA-mediated knockdown of PVN PACAP attenuated the development of SNL-induced anxiety- but not depressive-like behavior. Our data support that PVN PACAP signaling is involved in an important mechanism underlying the anxiety-like behaviors in peripheral neuropathic pain condition.