A novel rat model of temporomandibular disorder with improved face and construct validities.

AIMS: Temporomandibular disorders are a cluster of orofacial conditions that are characterized by pain in the temporomandibular joint (TMJ) and surrounding muscles/tissues. Animal models of painful temporomandibular dysfunction (TMD) are valuable tools to investigate the mechanisms responsible for symptomatic temporomandibular joint and associated structures disorders. We tested the hypothesis that a predisposing and a precipitating factor are required to produce painful TMD in rats, using the ratgnawmeter, a device that determines temporomandibular pain based on the time taken for the rat to chew through two obstacles. MATERIALS AND METHODS: Increased time in the ratgnawmeter correlated with nociceptive behaviors produced by TMJ injection of formalin (2.5%), confirming chewing time as an index of painful TMD. Rats exposed only to predisposing factors, carrageenan-induced TMJ inflammation or sustained inhibition of the catechol-O-methyltransferase (COMT) enzyme by OR-486, showed no changes in chewing time. However, when combined with a precipitating event, i.e., exaggerated mouth opening produced by daily 1-h jaw extension for 7 consecutive days, robust function impairment was produced. KEY FINDINGS: These results validate the ratgnawmeter as an efficient method to evaluate functional TMD pain by evaluating chewing time, and this protocol as a model with face and construct validities to investigate symptomatic TMD mechanisms. SIGNIFICANCE: This study suggests that a predisposition factor must be present in order for an insult to the temporomandibular system to produce painful dysfunction. The need for a combined contribution of these factors might explain why not all patients experiencing traumatic events, such as exaggerated mouth opening, develop TMDs.

The rostromedial tegmental nucleus: a key modulator of pain and opioid analgesia.

A recently defined structure, the rostromedial tegmental nucleus (RMTg; aka tail of the ventral tegmental area [VTA]), has been proposed as an inhibitory control center for dopaminergic activity of the VTA. This region is composed of GABAergic cells that send afferent projections to the ventral midbrain and synapse onto dopaminergic cells in the VTA and substantia nigra. These cells exhibit µ-opioid receptor immunoreactivity, and in vivo, ex vivo, and optogenetic/electrophysiological approaches demonstrate that morphine excites dopamine neurons by targeting receptors on GABAergic neurons localized in the RMTg. This suggests that the RMTg may be a key modulator of opioid effects and a major brake regulating VTA dopamine systems. However, no study has directly manipulated RMTg GABAergic neurons in vivo and assessed the effect on nociception or opioid analgesia. In this study, multiplexing of GABAergic neurons in the RMTg was achieved using stimulatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and inhibitory kappa-opioid receptor DREADDs (KORD). Our data show that locally infused RMTg morphine or selective RMTg GABAergic neuron inhibition produces 87% of the maximal antinociceptive effect of systemic morphine, and RMTg GABAergic neurons modulate dopamine release in the nucleus accumbens. In addition, chemoactivation of VTA dopamine neurons significantly reduced pain behaviors both in resting and facilitated pain states and reduced by 75% the dose of systemic morphine required to produce maximal antinociception. These results provide compelling evidence that RMTg GABAergic neurons are involved in processing of nociceptive information and are important mediators of opioid analgesia.