A Clinically Relevant Animal Model of Temporomandibular Disorder and Irritable Bowel Syndrome Comorbidity

Abstract

Temporomandibular disorders (TMD) and irritable bowel syndrome (IBS) are comorbid functional chronic pain disorders of unknown etiology that are triggered/exacerbated by stress. Here we present baseline phenotypic characterization of a novel animal model to gain insight into the underlying mechanisms that contribute to such comorbid pain conditions. In this model, chronic visceral hypersensitivity, a defining symptom of IBS, is dependent upon on three factors: estradiol, existing chronic somatic pain, and stress. In ovariectomized rats, estradiol replacement followed by craniofacial muscle injury and stress induced visceral hypersensitivity that persisted for months. Omission of any one factor resulted in a transient (1 week) visceral hypersensitivity from stress alone, or no hypersensitivity (no inflammation or estradiol). Maintenance of visceral hypersensitivity was estradiol dependent; resolving when estradiol replacement ceased. Referred cutaneous hypersensitivity was concurrent with visceral hypersensitivity. Increased spinal Fos expression suggests induction of central sensitization. These data demonstrate the development and maintenance of visceral hypersensitivity in estradiol-replaced animals following distal somatic injury and stress that mimics some characteristics reported in patients with TMD and comorbid IBS. This new animal model is a powerful experimental tool which can be employed to gain further mechanistic insight into overlapping pain conditions.

Extracellular signal‐regulated kinase activation in the spinal cord contributes to visceral hypersensitivity induced by craniofacial injury followed by stress

“…The experimental protocol was similar to our previous study and shown in Figure . Rats were anesthetized with isoflurane, ovariectomized (OVx) by a dorsolateral approach and subsequently single housed.…”

“…The bilateral masseter muscles were injected with complete Freund's adjuvant (CFA, 150 μL, 1:1 in saline; Sigma, St Louis, MO, USA) or saline (control for CFA injection). Subchronic stress was induced by a 3 day FS paradigm starting the following day . Rats were placed in a cylindrical container (30 cm diameter) filled to 20 cm with 25‐26 °C water.…”

“…Rats swam for 10 minutes on the first day and 20 minutes on the next 2 days. This stress model was chosen since it could be completed between E2 injections and within one 4‐day estrous cycle . The immobility time and fecal pellet output of rats was recorded during the first 10 minutes of each swim session.…”

“…Unfortunately, the mechanism accounting for the comorbidity between IBS and TMD is unclear, and this is reflected in less than optimal treatments for associated pain. Recently, we developed an animal model in which masseter muscle inflammation followed by 3 day forced swim (FS) stress induces chronic visceral hypersensitivity, a characteristic symptom of IBS . This model provides a platform to examine the mechanisms of overlapping pain in IBS and TMD.…”

Inflammatory ‘double hit’ model of temporomandibular joint disorder with elevated CCL2, CXCL9, CXCL10, RANTES and behavioural hypersensitivity in TNFR1/R2−/− mice

“…Bacterial degradation products, their cell walls and DNA, have been identified in synovial fluids from patients with TMD, RA, and reactive arthritis (Klineberg et al, 1998; Toivanen, 2001; Chen et al, 2002; Olsen-Bergem et al, 2016). Multiple experimental studies have demonstrated dysregulated TNFα and malfunctioning TNFR1 and TNFR2 caused by inflammation (Peschon et al, 1998; Kagari et al, 2002; Choi et al, 2010), or neuropathy (Sommer and Kress, 2004), as well as by “double-hit” inflammatory insults that can cause chronic inflammation not only in joints (Hains et al, 2010; Westlund et al, 2012; Traub et al, 2014) but also in other organs (Mariotti et al, 2002; Ilievski and Hirsch, 2010). The first inflammatory insult primes the immune system so that subsequent insults elicit amplified responses (Rubin and Coons, 1972).…”