Predicting the therapeutic effect of carbamazepine in trigeminal neuralgia by analysis of neurovascular compression utilizing magnetic resonance cisternography.

The aim of this study was to determine whether the evaluation of neurovascular compression (NVC) using new criteria on magnetic resonance (MR) cisternography improves the prediction of the curative effects of carbamazepine (CBZ) in trigeminal neuralgia (TN). In this study, a new analysis of NVC using MR cisternography was performed retrospectively for 280 patients with clinical signs and symptoms suggesting TN. The new analysis examined whether the site of the NVC was less than 3mm from the edge of the exit point and within the first third of the root entry zone on MR cisternography. Prediction of the curative effects of CBZ using the new evaluation of distance to the NVC improved on the predictive ability of the previous method of calculating the NVC volume (Mantel-Haenszel coefficient, P<0.01). In particular, initial treatment with CBZ 100mg/day for 2 weeks appeared more effective for patients with NVC volumes of ≤5mm3 plus a distance to the NVC of ≤3mm, than for those with NVC volumes >5mm3. The evaluation of NVC on MR cisternography using this new approach appears to be more useful than the previous method for predicting the initial treatment response in patients with TN.

Endothelin-1 Elicits TRP-Mediated Pain in an Acid-Induced Oral Ulcer Model.

Oral ulcer is the most common oral disease and leads to pain during meals and speaking, reducing the quality of life of patients. Recent evidence using animal models suggests that oral ulcers induce cyclooxygenase-dependent spontaneous pain and cyclooxygenase-independent mechanical allodynia. Endothelin-1 is upregulated in oral mucosal inflammation, although it has not been shown to induce pain in oral ulcers. In the present study, we investigated the involvement of endothelin-1 signaling with oral ulcer-induced pain using our proprietary assay system in conscious rats. Endothelin-1 was significantly upregulated in oral ulcers experimentally induced by topical acetic acid treatment, while endothelin-1 production was suppressed by antibacterial pretreatment. Spontaneous nociceptive behavior in oral ulcer model rats was inhibited by swab applications of BQ-788 (ETB receptor antagonist), ONO-8711 (prostanoid receptor EP1 antagonist), and HC-030031 (TRPA1 antagonist). Prostaglandin E2 production in the ulcers was suppressed by BQ-788. Mechanical allodynia in the model was inhibited not only by BQ-788 and HC-030031 but also by BQ-123 (ETA receptor antagonist), SB-366791 (TRPV1 antagonist), and RN-1734 (TRPV4 antagonist). In naive rats, submucosal injection of endothelin-1 caused mechanical allodynia that was sensitive to HC-030031 and SB-366791 but not to RN-1734. These results suggest that endothelin-1 production following oral bacterial invasion via ulcerative regions elicits TRPA1-mediated spontaneous pain. This pain likely occurs through an indirect route that involves ETB receptor-accelerated prostanoid production. Endothelin-1 elicits directly TRPA1- and TRPV1-mediated mechanical allodynia via both ETA and ETB receptors on nociceptive fibers. The TRPV4-mediated allodynia component seems to be independent of endothelin signaling. These findings highlight the potential of endothelin signaling blockers as effective analgesic approaches for oral ulcer patients.

Endothelin receptor-mediated responses in trigeminal ganglion neurons.

Recent evidence implicates endothelin in nociception, but it is unclear how endothelin activates trigeminal ganglion (TRG) neurons. In the present study, we investigated the expression of the endothelin receptors ETA and ETB and endothelin-induced responses in rat TRG neurons. Double-immunofluorescence studies demonstrated that ETA and ETB were expressed in TRG neurons and that 26% of ETA- or ETB-expressing neurons expressed both receptors. During whole-cell patch-clamp recording, endothelin-1 enhanced an induced current in response to capsaicin, a TRPV1 agonist, in approximately 20% of dissociated neurons. The enhancement was blocked by the PKC inhibitor chelerythrine and by the ETA antagonist BQ-123, but not by the ETB antagonist BQ-788. Ca(2+)-imaging showed that endothelin-1 increased the intracellular Ca(2+) concentration in more than 20% of the dissociated neurons. Importantly, unlike the effect of endothelin-1 on capsaicin-induced current, the Ca(2+) response was largely suppressed by BQ-788 but not by BQ-123. These results suggest that ETA-mediated TRPV1 hyperactivation via PKC activation and ETB-mediated Ca(2+) mobilization occurs in different subsets of TRG neurons. These endothelin-induced responses may contribute to the induction of orofacial pain. The ETB-mediated function in TRG neurons is a special feature in the trigeminal system because of no ETB expression in dorsal root ganglion neurons.

Central glial activation mediates cancer-induced pain in a rat facial cancer model.

Peripheral and central glial activation plays an important role in development of pain hypersensitivity induced by inflammation and nerve injury. However, the involvement of glial cells in cancer pain is not well understood. The present study evaluated the peripheral and central glial activation and the effect of an inhibitor of glial activation, propentofylline, on pain-related behaviors in a rat facial cancer model of the growth of Walker 256B cells in the unilateral vibrissal pad until days 3-4 post-inoculation. As compared with sham animals, the facial grooming period was prolonged, the withdrawal latency to radiant heat stimulation was shortened, and the withdrawal threshold by von Frey hair stimulation was decreased at the inoculated region, indicating the development of spontaneous pain, thermal hyperalgesia and mechanical allodynia. In immunostainings for Iba1 and glial fibrillary acidic protein (GFAP), although there were no morphological changes of GFAP-immunopositive satellite glial cells in the trigeminal ganglion, Iba1-immunopositive microglia and GFAP-immunopositive astrocytes in the medullary dorsal horn showed large somata with cell proliferation. After the daily i.p. administration of propentofylline beginning pre-inoculation, the central glial activation was attenuated, the prolonged facial grooming was partially suppressed, and the induced allodynia and hyperalgesia from day 2 were prevented, without a change in tumor size. These results suggest that glial activation in the CNS, but not in the peripheral nervous system, mediates the enhancement of spontaneous pain and the development of allodynia and hyperalgesia at an early stage in the facial cancer model.

Differences between orofacial inflammation and cancer pain.

Rat models of orofacial cancer exhibit both allodynia and hyperalgesia; however, it is unclear whether cancer-induced pain is secondary to cancer-induced inflammation. To address this question, we compared the effects of an anti-inflammatory drug, indomethacin, on pain and neurochemical changes in the medullary dorsal horn in orofacial inflammation and cancer models. Daily peripheral administration of indomethacin largely suppressed mechanical allodynia and thermal hyperalgesia in the inflammation model. The same procedure suppressed allodynia and hyperalgesia in the cancer model, but the suppression was weak when compared with that in the inflammation model. In the medullary dorsal horn, calcitonin gene-related peptide and substance P levels were significantly increased in the inflammation model, but did not change in the cancer model. These results suggest that pain in the orofacial cancer model is not significantly mediated by cancer-induced peripheral inflammation, although it may have some involvement.