The present study is the first to investigate the participation of central cyclooxygenase (COX) pathways in modulating the antinociceptive effects of intracisternally administered cannabinoid on nociception induced by inflammation of the temporomandibular joint (TMJ) in freely moving rats. Following intra-articular injection of 5% formalin in the TMJ, nociceptive scratching behavior was recorded for nine successive 5-min intervals in Sprague-Dawley rats. Intracisternal injection of 30 microg of WIN 55,212-2, a synthetic non-subtype-selective CB1/2 agonist, administered 20 min prior to formalin injection significantly reduced the number of scratches and duration of scratching induced by formalin compared with the vehicle-treated group. Antinociceptive effect of WIN 55,212-2 was blocked by intracisternal injection of 10 microg of AM251, a CB1 receptor-selective antagonist, but not by AM630, a CB2 receptor-selective antagonist. A 10 microg dose of WIN 55,212-2 that was ineffective in producing antinociception became effective following intracisternal administration of NS-398, a selective COX-2 inhibitor; indomethacin, a non-selective COX 1/2 inhibitor; acetaminophen, a putative COX-3 inhibitor, but not following pretreatment with the selective COX-1 inhibitor, SC-560. The ED(50) value of WIN 55,212-2 in the NS-398-treated group was significantly lower than that in the vehicle-treated group. Importantly, administration of low doses of COX inhibitors alone did not attenuate nociception. These results indicate that inhibition of central COX pathways, presumably via COX-2 inhibition, reduces inflammatory pain by enhancing the cannabinoid-induced antinociceptive effect. Based on our observations, combined administration of cannabinoids with COX inhibitors may hold a therapeutic promise in the treatment of inflammatory TMJ pain.

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BackgroundWe investigated the role of the central NMDA receptor NR2 subunits in the modulation of nociceptive behavior and p-p38 MAPK expression in a rat model with compression of the trigeminal nerve root. To address this possibility, changes in air-puff thresholds and pin-prick scores were determined following an intracisternal administration of NR2 subunit antagonists. We also examined effects of NR2 subunit antagonists on the p-p38 MAPK expression.ResultsExperiments were carried out using male Sprague-Dawley rats weighing (200-230 g). Compression of the trigeminal nerve root was performed under pentobarbital sodium (40 mg/kg) anesthesia. Compression of the trigeminal nerve root produced distinct nociceptive behavior such as mechanical allodynia and hyperalgesia. Intracisternal administration of 10 or 20 μg of D-AP5 significantly increased the air-puff threshold and decreased the pin-prick scores in a dose-dependent manner. The intracisternal administration of PPPA (1, 10 μg), or PPDA (5, 10 μg) increased the air-puff threshold and decreased the pin-prick scores ipsilateral as well as contralateral to the compression of the trigeminal root. Compression of the trigeminal nerve root upregulated the expression of p-p38 MAPK in the ipsilateral medullary dorsal horn which was diminished by D-AP5, PPPA, PPDA, but not Ro25-6981.ConclusionsOur findings suggest that central NMDA receptor NR2 subunits play an important role in the central processing of trigeminal neuralgia-like nociception in rats with compression of the trigeminal nerve root. Our data further indicate that the targeted blockade of NR2 subunits is a potentially important new treatments strategy for trigeminal neuralgia-like nociception.

The present study investigated the role of peripheral opioid receptors in mustard oil-induced nociceptive behavior and inflammation in the masseter muscles of lightly anesthetized rats. Experiments were carried out on male Sprague-Dawley rats weighing between 300 and 400 g. After initial anesthesia with sodium pentobarbital (40 mg/kg, i.p.), one femoral vein was cannulated and connected to an infusion pump for the intravenous infusion of sodium pentobarbital. The rate of infusion was adjusted to provide a constant level of anesthesia. Mustard oil (MO, 30 microl) was injected into the mid-region of the left masseter muscle via a 30-gauge needle. Intramuscularly-administered morphine significantly reduced shaking behavior but not MO-induced inflammation. Intramuscular pretreatment with naloxone, an opioid receptor antagonist, reversed antinociception produced by intramuscularly-administered morphine, while intracisternal administration of naloxone did not affect the antinociception of peripheral morphine. Pretreatment with d-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a mu opioid receptor antagonist, but not naltrindole, a delta opioid receptor antagonist, nor norbinaltorphimine (nor-BNI), a kappa opioid receptor antagonist, reversed intramuscularly-administered morphine-induced antinociception. These results indicate that intramuscularly-administered morphine produces antinociception in craniofacial muscle nociception and that this intramuscularly-administered morphine-induced antinociception is mediated by a peripheral mu opioid receptor. Our observations further support the clinical approach of administering opioids in the periphery for the treatment of craniofacial muscle nociception.