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.

Differential Activation of Colonic Afferents and Dorsal Horn Neurons Underlie Stress-Induced and Comorbid Visceral Hypersensitivity in Female Rats.

Chronic Overlapping Pain Conditions, including irritable bowel syndrome (IBS) and temporomandibular disorder (TMD), represent a group of idiopathic pain conditions that likely have peripheral and central mechanisms contributing to their pathology, but are poorly understood. These conditions are exacerbated by stress and have a female predominance. The presence of one condition predicts the presence or development of additional conditions, making this a significant pain management problem. The current study was designed to determine if the duration and magnitude of peripheral sensitization and spinal central sensitization differs between restraint stress-induced visceral hypersensitivity (SIH) and chronic comorbid pain hypersensitivity (CPH; stress during pre-existing orofacial pain). SIH in female rats, as determined by the visceromotor response, persisted at least four but resolved by seven weeks. In contrast, CPH persisted at least seven weeks. Surprisingly, colonic afferents in both SIH and CPH rats were sensitized at seven weeks. CPH rats also had referred pain through seven weeks, but locally anesthetizing the colon only attenuated the referred pain through four weeks, suggesting a transition to colonic afferent independent central sensitization. Different phenotypes of dorsal horn neurons were sensitized in the CPH rats seven weeks post stress compared to four weeks or SIH rats. The current study suggests differential processing of colonic afferent input to the lumbosacral spinal cord contributes to visceral hypersensitivity during comorbid chronic pain conditions. PERSPECTIVE: Chronic Overlapping Pain Conditions represent a unique challenge in pain management. The diverse nature of peripheral organs hinders a clear understanding of underlying mechanisms accounting for the comorbidity. This study highlights a mismatch between the condition-dependent behavior and peripheral and spinal mechanisms that contribute to visceral pain hypersensitivity.