Distinct Functional Role of the Brainstem in Reflexive and Aversive Responses to Noxious Colorectal Distension

Abstract

Noxious colorectal distension (CRD) produces reflexive visceromotor responses (VMRs)and aversive responses through activation of supraspinal circuits. However, the specific role of brainstem regions in mediating these two colorectal pain-related responses remains unclear. To address this gap in the literature, we tested the functional relevance of five brainstem regions — the gracile nucleus (Gr), nucleus tractus solitarius (NTS), lateral parabrachial nucleus (lPBN), ventrolateral periaqueductal gray (VLPAG), and rostral ventromedial medulla (RVM) — in CRD- induced VMRs and aversive responses. We found that the Gr mediates reflexive but not aversive responses, while the NTS is required for aversive but not reflexive responses. The lPBN exhibited sex-dependent involvement, as it mediated reflexive responses in females and aversive responses in both sexes. These findings support the hypothesis that reflexive and aversive components of visceral pain are processed by dissociable brainstem circuits. Additionally, activation of descending modulatory structures, including the VLPAG and RVM, reduced reflexive responses. RVM excitation also impaired aversive learning, indicating its influence on affective components of pain. Importantly, aversive learning did not correlate with VMR magnitude, reinforcing the functional separation of these responses. Future studies of visceral pain should assess both response types independently when evaluating therapeutic targets or brain region function.