Sex differences in visceral sensitivity and brain activity in a rat model of comorbid pain: a longitudinal study

Abstract

Temporomandibular disorder (TMD) and irritable bowel syndrome (IBS) are 2 chronic overlapping pain conditions (COPCs) that present with significant comorbidity. Both conditions are more prevalent in women and are exacerbated by stress. While peripheral mechanisms might contribute to pain hypersensitivity for each individual condition, mechanisms underlying the comorbidity are poorly understood, complicating pain management when multiple conditions are involved. In this study, longitudinal behavioral and functional MRI-based brain changes have been identified in an animal model of TMD-like pain (masseter muscle inflammation followed by stress) that induces de novo IBS-like comorbid visceral pain hypersensitivity in rats. In particular, data indicate that increased activity in the insula and regions of the reward and limbic systems are associated with more pronounced and longer-lasting visceral pain behaviors in female rats, while the faster pain resolution in male rats may be due to increased activity in descending pain inhibitory pathways. These findings suggest the critical role of brain mechanisms in chronic pain conditions and that sex may be a risk factor of developing COPCs.

Pathology of pain and its implications for therapeutic interventions

“…The ascending pain transduction tracts are more engaged in preventing pain habituation in males. 442 The regulatory signals from the CeA project to the ventrolateral PAG (vPAG). Inflammatory pain can induce overactivation of the CeA-vPAG pathway in females, resulting in more severe chronic pain sensations.…”

Sex Differences in Visceral Pain and Comorbidities: Clinical Outcomes, Preclinical Models, and Cellular and Molecular Mechanisms

“…As for rWAS (1 h stress daily for a consecutive 4 days), visceral motor responses (VMR) is increased in female rats but not male rats in response to 60 mmHg colorectal distension (CRD) examined 24 h post rWAS [63]. A study in rat TMD disorder that has IBS comorbidity also shows stronger and longer-lasting visceral pain behaviors in female rats than male rats [66]. These rat models with stress are valuable tools in investigating the molecular mechanisms of sex-dependent non-inflammation-related nociplastic visceral pain.…”