Background & Aims

Temporomandibular disorder (TMD) and irritable bowel syndrome (IBS) are two chronic overlapping pain conditions (COPCs) that present with significant comorbidity. Both conditions are more prevalent in women [1][2] and are exacerbated by stress [3]. While peripheral mechanisms might contribute to pain hypersensitivity for each individual condition, mechanisms underlying the comorbidity are poorly understood. It has been suggested that pain amplification in COPCs is the result of dysfunctional CNS pain processing caused by altered connectivity among several brain regions, including the insula. Nonpharmacological therapies such as Environmental Enrichment (EE) have been shown to reduce pain- and anxiety-like behaviors, enhance learning and memory, and induce neural plasticity. We have developed a mouse model of comorbid pain hypersensitivity (CPH: stress during preexisting orofacial pain) and examined the effects of EE on behavioral and brain connectivity changes induced by this model.

Methods

Eighteen female mice were divided into 3 groups: 6 CPH + EE, 6 CPH only, and 6 naive mice. Masseter muscles were injected with Complete Freund’s Adjuvant one day prior to initiating the stress protocol (2 days of restraint stress for 2 hours in confining tubes alternating with 2 days 20 min forced swim stress). The day following the last stress session was designated as day 1. Baseline data were collected prior to the CFA injection/restraint stress. Referred pain (visceral pain correlate) was measured as the increase in responsiveness to von Frey stimulation of the lower abdomen above baseline mechanosensitivity following inflammation and stress. All mice underwent resting-state fMRI scans 1 week after day 1. A seed-based correlation analysis approach was used to determine changes in insula connectivity to the whole brain in relation to CPH and how EE affects this relationship. Network analysis determined ROI-to-ROI functional connectivity differences across the 3 groups.

Results

CPH increased referred pain in female mice for at least 4 weeks. EE blocked the referred pain development. Contrast map results (p < 0.05) showed EE mice exhibited lower insula connectivity to the following regions compared to CPH mice: Claustrum, Caudoputamen, Central medial nucleus of the thalamus, Central amygdalar nucleus, medial part. In addition, CPH mice with EE showed increased connectivity between insula and periaqueductal gray, which is similarly seen in naive mice compared to CPH group. Network analysis (p < 0.05) revealed EE and Naive mice both exhibited lower node degree (number of connections to an ROI) and/or node strength (sum of edge weights connected to an ROI) than CPH mice to the following regions: Right Hippocampal Formation, Right Agranular Insular Area Posterior and Right Primary Somatosensory Area Barrel Field. EE and Naive mice showed higher node degree and/or node strength than CPH mice in the Right Supraoculomotor Periaqueductal Gray.

Conclusions

These results demonstrate that EE can reduce referred pain and functional connectivity of areas involved in pain and stress processing and may be strengthening the impaired endogenous pain inhibitory system seen in comorbid pain conditions. Further experiments are currently being done to fully investigate the effects of EE on comorbid pain conditions and potential sex differences.

References

[1] Maixner W, Fillingim RB, Williams DA, Smith SB, Slade GD. Overlapping Chronic Pain Conditions: Implications for Diagnosis and Classification. J Pain. 2016 Sep;17(9 Suppl):T93-T107. doi: 10.1016/j.jpain.2016.06.002. PMID: 27586833; PMCID: PMC6193199.

[2] Sharma S, Slade GD, Fillingim RB, Greenspan JD, Rathnayaka N, Ohrbach R. Attributes Germane to Temporomandibular Disorders and Their Associations with Five Chronic Overlapping Pain Conditions. J Oral Facial Pain Headache. 2020;34(Suppl):s57-s72. doi: 10.11607/ofph.2582. PMID: 32975541; PMCID: PMC10073965.

[3] Da Silva JT, Hernandez-Rojas LG, Mekonen HK, Hanson S, Melemedjian O, Scott AJ, Ernst RK, Seminowicz DA, Traub RJ. Sex differences in visceral sensitivity and brain activity in a rat model of comorbid pain: a longitudinal study. Pain. 2023 Sep 27. doi: 10.1097/j.pain.0000000000003074. Epub ahead of print. PMID: 37756658.

Presenting Author

Michael L. Keaser

Poster Authors

Michael Keaser

Bachelor of Arts

University of Maryland School of Dentistry

Lead Author

E-mail

Topics

  • Pain Imaging