The aim of the present study was to develop an animal model for evaluation of temporomandibular (TMJ) nociception under TMJ inflammation. We also investigated the participation of IL-1β in inflammation-induced TMJ nociception. Experiments were carried out using male Sprague-Dawley rats. Intra-articular injection of 3% formalin was administered to evaluate hyperalgesia 3 days after CFA injection. Intra-articular injection of 3% formalin did not produce nociceptive behavior in normal rats. Although intra-articular injection of 3 doses of CFA produced TMJ inflammation, only 1:3 diluted CFA produced hyperalgesia when formalin was injected intra-articularly 3 days after CFA injection. Co-administration of IL-1 receptor inhibitor with formalin into the TMJ cavity 3 days after CFA injection was performed. Co-administration of IL-1 receptor inhibitor significantly inhibited formalin-induced hyperalgesia in rats with CFA-induced TMJ inflammation. These results suggested that intra-articular injection of formalin produced hyperalgesia under chronic TMJ inflammation. Moreover, IL-1β plays an important role in TMJ hyperalgesia under chronic inflammation and blockade of IL-1β is a potential therapeutic target for inflammatory TMJ pain.

The present study investigated the role of central GABAA and GABAB receptors in orofacial pain in rats. Experiments were conducted on Sprague-Dawley rats weighing between 230 and 280 g. Intracisternal catheterization was performed for intracisternal injection, under ketamine anesthesia. Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia and inferior alveolar nerve injury-induced mechanical allodynia were employed as orofacial pain models. Intracisternal administration of bicuculline, a GABAA receptor antagonist, produced mechanical allodynia in naive rats, but not thermal hyperalgesia. However, CGP35348, a GABAB receptor antagonist, did not show any pain behavior in naive rats. Intracisternal administration of muscimol, a GABAA receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. On the contrary, intracisternal administration of bicuculline also attenuated the mechanical allodynia in rats with inferior alveolar nerve injury. Intracisternal administration of baclofen, a GABAB receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. In contrast to GABAA receptor antagonist, intracisternal administration of CGP35348 did not affect either the thermal hyperalgesia or mechanical allodynia. Our current findings suggest that the GABAA receptor, but not the GABAB receptor, participates in pain processing under normal conditions. Intracisternal administration of GABAA receptor antagonist, but not GABAB receptor antagonist, produces paradoxical antinociception under pain conditions. These results suggest that central GABA has differential roles in the processing of orofacial pain, and the blockade of GABAA receptor provides new therapeutic targets for the treatment of chronic pain.

The present study investigated the role of peripheral P2X receptors in inflammatory pain transmission in the orofacial area in rats. Experiments were carried out on male Sprague- Dawley rats weighing 220 to 280 g. Formalin (5%, 50 μL) and complete Freund's adjuvant (CFA, 25 μL) was applied subcutaneously to the vibrissa pad to produce inflammatory pain. TNP-ATP, a P2X2,2/3,4 receptor antagonist, or OX-ATP, a P2X7 receptor antagonist, was then injected subcutaneously at 20 minutes prior to formalin injection. One of the antagonists was administered subcutaneously at three days after CFA injection. The subcutaneous injection of formalin produced a biphasic nociceptive behavioral response. Subcutaneous pretreatment with TNP-ATP (80, 160 or 240 μg) significantly suppressed the number of scratches in the second phase produced by formalin injection. The subcutaneous injection of 50 μg of OX-ATP also produced significant antinociceptive effects in the second phase. Subcutaneous injections of CFA produced increases in mechanical and thermal hypersensitivity. Both TNP-ATP (480 μg) and OX-ATP (100 μg) produced an attenuation of mechanical hypersensitivity. However, no change was observed in thermal hypersensitivity after the injection of either chemical. These results suggest that the blockade of peripheral P2X receptors is a potential therapeutic approach to the onset of inflammatory pain in the orofacial area.

It has been well known that excitatory amino acids, primarily glutamate, are involved in the transmission of nociception in pathological and physiological conditions in the spinal and brainstem level. Recently, peripheral glutamate also play a critical role in the peripheral nociceptive transmissions. The present study investigated the role of N-methyl-D-aspartic acid (NMDA) or non-NMDA ionotropic glutamate receptors in formalin-induced TMJ pain. Experiments were carried out on male Sprague-Dawley rats weighing 220-280 g. Intra-articular injection was performed under halothane anesthesia. Under anesthesia, AP-7 (10, 100μM, 1mM/20 μL), a NMDA receptor antagonist, or CNQX disodium salt (0.5, 5, 50, 500 μM/20 μL), a non-NMDA receptor antagonist, were administered intra-articularly 10 min prior to the application of 5% formalin. For each animal, the number of behavioral responses, such as rubbing and/or scratching the TMJ region, was recorded for nine successive 5-min intervals. Intra-articular pretreatment with 1 mM of AP-7 or 50 μM CNQX significantly decreased the formalin-induced scratching behavioral responses during the second phase. Intra-articular pretreatment with 500μM of CNQX significantly decreased the formalin-induced scratching behavior during both the first and the second phase. These results indicate that the intra-articular administration of NMDA or non-NMDA receptor antagonists inhibit formalin-induced TMJ nociception, and peripheral ionotropic glutamate receptors may play an important role in the TMJ nociception.

To develop a clinically available saponin- or sapogenin complex from Oriental medicines, the EtOH extract (KPRG-A) was obtained by extracting from the four crude drugs, Kalopanacis Cortex, Platycodi Radix, Rubi Fructus and Glycyrrhizae Radis. The BuOH fraction (KPRG-B), a crude saponin complex, was prepared by fractionating KPRG-A, which were further completely hydrolyzed to afford the sapogenin complex (KPRG-D). In an attempt to find the antinoicpetive effects of the saponin complex and sapogenin complex, KPRG-C, and -D, were assayed by writhing-, hot plate-, and tail-flick tests using mice or rats. The three samples were also subjected to antiiflammatory tests using serotonin-induced and carrageenan-induced hind paw edema mice and rats, respectively. The three samples significantly reduced inflammations and pains of the experimental animal. The potency were found in the order of KPRG-D> KPRG-C> KPRG-B. The most active sample, KPRG-D, caused no death, no body increase or no anatomical pathlogic change even at 2,000 mg/kg dose. These results suggest that a sapogenin complex, KPRG-D, which was found to contain mainly hederagenin, platycodigenin, polygalacic acid, 23-hydroxytormentic acid, glycyrrhetic acid together with minor triterpene acids, could be a potential candidate for antiinflammatory therapeutics.