We have previously reported a novel method for producing chronic nociceptive behavior in rats following compression of the trigeminal ganglion. In the present study, we have further studied the role of demyelination in the development of prolonged nociceptive behavior in the trigeminal territory. For this purpose, lysophosphatidic acid (LPA) was injected into the trigeminal ganglia of male Sprague-Dawley rats weighing between 250 and 260 g. Under pentobarbital sodium anesthesia, the rats were mounted onto a stereotaxic frame and 3 microL of LPA (1 nmol) solution was injected into the trigeminal ganglion to produce demyelination. This treatment decreased the air-puff thresholds both ipsilateral and contralateral to the injection site, which persisted until postoperative day 100 and returned to the preoperative levels 130 days after the LPA injection. The LPA injection also produced a significant ipsilateral hyper-responsiveness to pin-prick stimulation. The effects of DGPP, an LPA1/3 receptor antagonist, and Y-27632, a Rho kinase inhibitor, upon LPA-induced mechanical allodynia and hyperalgesia were also investigated. Pretreatment with DGPP blocked both mechanical allodynia and ipsilateral hyperalgesia. However, pretreatment with Y-27632 blocked only ipsilateral and contralateral mechanical allodynia. These results thus indicate that a targeted blockade of LPA receptor and Rho kinase pathways are potentially important new treatments for demyelination-induced trigeminal neuralgia-like nociception.

Background: We investigated the differential regulation of p-p38 MAPK or p-NF- κB in male Sprague-Dawley rats with inferior alveolar nerve injury resulting from mal-positioned dental implants. For this purpose, we characterized the temporal expression of p-p38 MAPK or p-NF- κB in the medullary dorsal horn and examined changes in nociceptive behavior after a blockade of p-p38 MAPK or p-NF- κB pathways in rats with trigeminal neuropathic pain. Results: Under anesthesia, the left lower second molar was extracted and replaced with a mini dental implant to intentionally injure the inferior alveolar nerve. Western and immunofluorescence analysis revealed that p-p38 MAPK is upregulated in microglia following nerve injury and that this expression peaked on postoperative day (POD) 3 through 7. However, the activation of p-NF- κB in astrocyte peaked on POD 7 through 21. The intracisternal administration of SB203580 (1 or 10 μg), a p38 MAPK inhibitor, on POD 3 but not on POD 21 markedly inhibits mechanical allodynia and the p-p38 MAPK expression. However, the intracisternal administration of SN50 (0.2 or 2 ng), an NF- κB inhibitor, on POD 21 but not on POD 3 attenuates mechanical allodynia and p-NF- κB expression. Dexamethasone (25 mg/kg) decreases not only the activation of p38 MAPK but also that of NF- κB on POD 7. Conclusions: These results suggest that early expression of p-p38 MAPK in the microglia and late induction of p-NF- κB in astrocyte play an important role in trigeminal neuropathic pain and that a blockade of p-p38 MAPK at an early stage and p-NF- κB at a late stage might be a potential therapeutic strategy for treatment of trigeminal neuropathic pain.

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.

The analgesic effects of dexamethasone on neuropathic pain have been controversial. The present study investigated the effects of dexamethasone on mechanical allodynia in rats with mal-positioned dental implants. Under anesthesia, the left mandibular second molar was extracted and replaced by a miniature dental implant to injure the inferior alveolar nerve. Nociceptive behavior was examined on each designated day after surgery. Mal-positioned dental implants significantly decreased air-puff thresholds both ipsilateral and contralateral to the injury site. Distinct mechanical hyperalgesia and cold and thermal hypersensitivity were also observed bilaterally. Daily administration of dexamethasone produced prolonged anti-allodynic effects (25 or 50 mg/kg, i.p.), but failed to reduce mechanical allodynia when it had already been established. Therefore, our findings provide that early treatment with dexamethasone is important in the treatment of nociceptive behavior suggestive of trigeminal neuropathic pain.

Previous studies have demonstrated that botulinum toxin type A (BoNT-A) attenuates orofacial nociception. However, there has been no evidence of the participation of the voltage-gated sodium channels (Navs) in the antinociceptive mechanisms of BoNT-A. This study investigated the cellular mechanisms underlying the antinociceptive effects of BoNT-A in a male Sprague-Dawley rat model of trigeminal neuropathic pain produced by malpositioned dental implants. The left mandibular second molar was extracted under anesthesia, followed by a miniature dental implant placement to induce injury to the inferior alveolar nerve. Mechanical allodynia was monitored after subcutaneous injection of BoNT-A at 3, 7, or 12 d after malpositioned dental implant surgery. Subcutaneous injections of 1 or 3 U/kg of BoNT-A on postoperative day 3 significantly attenuated mechanical allodynia, although 0.3 U/kg of BoNT-A did not affect the air-puff threshold. A single injection of 3 U/kg of BoNT-A produced prolonged antiallodynic effects over the entire experimental period. Treatment with BoNT-A on postoperative days 7 and 12, when pain had already been established, also produced prolonged antiallodynic effects. Double treatments with 1 U/kg of BoNT-A produced prolonged, more antiallodynic effects as compared with single treatments. Subcutaneous administration of 3 U/kg of BoNT-A significantly inhibited the upregulation of Nav isoform 1.7 (Nav1.7) expression in the trigeminal ganglion in the nerve-injured animals. These results suggest that antinociceptive effects of BoNT-A are mediated by an inhibition of upregulated Nav1.7 expression in the trigeminal ganglion. BoNT-A is therefore a potential new therapeutic agent for chronic pain control, including neuropathic pain.