Local blockade of integrins in the temporomandibular joint region reduces Fos-positive neurons in trigeminal subnucleus caudalis of female rats produced by jaw movement.

This study assessed the influence of integrins on trigeminal brainstem neural activity evoked during jaw movement (JM). Limited range of motion and pain during jaw opening are common complaints of patients with temporomandibular joint (TMJ) disorders. JM (0.5 Hz, 30 min) was presented to ovariectomized (OvX) female rats given estrogen replacement and males under barbiturate anesthesia. Quantification of Fos-like immunoreactivity (Fos-LI) after JM served as an index of evoked neural activity. Rats were injected locally in the TMJ with either an active (GRGDS, 300 microM, 25 microl) or an inactive integrin antagonist (SDGRG) prior to JM. The effect of prior inflammation of the TMJ region was assessed in separate groups of rats by injecting bradykinin (10 microM, 25 microl) with or without integrin drugs prior to JM. Active integrin antagonist significantly reduced JM-evoked Fos-LI in superficial laminae at the trigeminal subnucleus caudalis/upper cervical cord (Vc/C2) junction in OvX compared to male rats independent of bradykinin pretreatment. Fos-LI produced in the dorsal paratrigeminal and trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition regions was not reduced by active integrin antagonist in males or OvX females. Active integrin antagonist did not affect Fos-LI produced after injection of bradykinin alone into the TMJ. These results suggest that RGD binding integrins contribute to JM-evoked neural activity at the Vc/C2 junction under naive and inflamed conditions in a sex-dependent manner.

Effect of persistent monoarthritis of the temporomandibular joint region on acute mustard oil-induced excitation of trigeminal subnucleus caudalis neurons in male and female rats.

The effect of persistent inflammation of the temporomandibular (TMJ) region on Fos-like immunoreactivity (Fos-LI) evoked by acute noxious stimulation of the same or opposite TMJ was assessed in male and cycling female rats. Two weeks after inflammation of the TMJ by complete Freund's adjuvant (CFA, 25 microg) the selective small fiber excitant, mustard oil (MO, 20%), was injected into the arthritic or opposite TMJ under barbiturate anesthesia. MO stimulation of the arthritic TMJ increased Fos-LI ipsilateral, but not contralateral, to MO compared to naïve subjects in superficial laminae at the trigeminal subnucleus caudalis/upper cervical cord (Vc/C2) junction independent of sex hormone status. Unexpectedly, MO stimulation of the opposite TMJ in arthritic rats also produced a greater Fos-LI response ipsilateral to MO than naïve animals. Fos-LI produced in the dorsal paratrigeminal region (dPa5) and Vc/C2 junction after MO stimulation of the normal TMJ was significantly greater in proestrous than diestrous females or male monoarthritic rats. In contrast to naïve animals, Fos-LI was produced in deep laminae at the Vc/C2 junction ipsilateral to MO in CFA-treated animals independent of the site of prior CFA inflammation or sex hormone status. These results indicated that persistent monoarthritis of the TMJ region enhanced the excitability of trigeminal brainstem neurons to subsequent TMJ injury that occurred bilaterally in multiple regions of the lower trigeminal brainstem complex and depended on sex hormone status.

Vagotomy prevents morphine-induced reduction in Fos-like immunoreactivity in trigeminal spinal nucleus produced after TMJ injury in a sex-dependent manner.

Acute injury to the temporomandibular joint (TMJ) region activates neurons in multiple, but spatially discrete, areas of the trigeminal spinal nucleus as seen by an increase in Fos-like immunoreactive neurons (Fos-LI). Pretreatment with morphine greatly reduces Fos-LI produced in the dorsal paratrigeminal area (dPa5), ventrolateral pole of the subnucleus interpolaris/caudalis (Vi/Vc-vl) transition region, and laminae I-II at the subnucleus caudalis/upper cervical cord junction (Vc/C2) suggesting a role for these areas in processing pain signals from the TMJ region. To determine if vagal afferents contribute to neural activation after TMJ injury or reduction of activity after morphine, Fos-LI was quantified in the lower brainstem and upper cervical spinal cord of intact and vagotomized male and female rats under barbiturate anesthesia. Bilateral cervical vagotomy (VgX) did not affect Fos-LI produced by TMJ injury in males or females in the absence of morphine. By contrast, morphine-induced reduction in Fos-LI produced at the Vi/Vc-vl transition region was prevented by prior VgX in males and diestrus females, but not in proestrus females. Morphine inhibition of Fos-LI produced in laminae I-II at the Vc/C2 junction region was diminished in vagotomized males compared to intact animals, but not affected in females. In an autonomic control area, the caudal ventrolateral medulla (CVLM), VgX reversed the morphine-induced reduction in Fos-LI in males and females similarly compared to their respective intact controls. These results were consistent with the hypothesis that the Vi/Vc-vl transition region plays a unique role in deep craniofacial pain processing and may integrate autonomic and opioid-related modulatory signals in a manner dependent on sex hormone status.

The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity in central trigeminal neurons and blocks select endocrine and autonomic responses to corneal stimulation in the rat.

The N-methyl-D-aspartate (NMDA) receptor is implicated in multiple aspects of pain processing by the central nervous system. However, the role of NMDA receptors in the endocrine and autonomic aspects of nociception remains uncertain. The present study examined the influence of the NMDA receptor antagonist, MK-801 (0.02-2.0 mg/kg, intracarotid), on the adrenal and autonomic responses to corneal stimulation (mustard oil, 20% sol.) in barbiturate-anesthetized rats. Fos-like immunoreactivity (Fos-LI) evoked by corneal stimulation was quantified within the spinal trigeminal nucleus (Vsp) of MK-801 pretreated animals to assess activation of central trigeminal neurons. Corneal stimulation-evoked increases in the plasma concentrations of adrenocorticotropin (ACTH), epinephrine and norepinephrine were reduced dose-dependently by MK-801. Plasma ACTH also increased after moderate hemorrhage, a response that was not affected by MK-801. MK-801 did not reduce the magnitude of corneal stimulation-evoked increases in arterial pressure and heart rate; however, prestimulus arterial pressure was reduced by drug treatment. Fos-LI was distributed bimodally within the ipsilateral caudal Vsp: one peak of Fos-LI in the subnucleus interpolaris/caudalis transition region and a second peak within the superficial laminae of the subnucleus caudalis/upper cervical cord transition region. The magnitude of both peaks of Fos-LI was reduced dose-dependently by MK-801. These results indicate a significant contribution from NMDA receptors in control of select endocrine and autonomic responses that accompany trigeminal nociception and in activation of central trigeminal neurons that process corneal nociceptive input.