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.
Animals ; Formaldehyde ; Humans ; Hyperalgesia ; Inflammation* ; Injections, Intra-Articular ; Interleukin-1 ; Male ; Models, Animal ; Nociception* ; Rats* ; Rats, Sprague-Dawley ; Temporomandibular Joint

No abstract available.
Kidney* ; Transplants* ; Tuberculosis*

The present study was performed to investigate the effects of intra-articular injection of interleukin-1beta (IL-1beta) on the formalin-induced temporomandibular joint (TMJ) pain. Under anesthesia, a 30-gauge needle was introduced into the right TMJ region for injection of formalin. Microinjection of 50 microliter of 5% formalin significantly produced noxious scratching behavioral response, and the scratching behavior lasted for 40 min. Although the responses produced by formalin injection were divided into two phases, the response of 1st phase did not significantly differ from the scratching behavior response in the saline-treated group. We examined the effects of intra-articular injection of IL-1beta on the number of noxious behavioral responses produced by 50microliter of 5% formalin injection. Intra-articular injection of 100 pg and 1 ng of IL-1beta significantly increased the number of behavioral responses of the 2nd phase, while 10 pg of IL-1beta did not change the formalin-induced behavioral responses. To investigate whether IL-1 receptor was involved in the intra-articular administration of IL-1beta-induced hyperalgesic response, IL-1 receptor antagonist (IL- ra, 50 ng) was administrated together with IL-1beta injection. IL-1beta receptor antagonist blocked IL-1beta- induced hyperalgesic response in the TMJ formalin test. These results suggest that intra-articular injection of IL-1beta facilitated the transmission of nociceptive information in the TMJ area.
Anesthesia ; Animals ; Cytokines ; Formaldehyde ; Hyperalgesia ; Injections, Intra-Articular* ; Interleukin-1 ; Interleukin-1beta ; Microinjections ; Needles ; Pain Measurement ; Rats* ; Temporomandibular Joint*

The study aimed to investigate the role of peripheral NLR family pyrin domain-containing 3 protein (NLRP3) in inflammatory pain development in the orofacial area. Male Sprague–Dawley rats were used in experiments, with orofacial formalin-induced pain behavior and complete Freund’s adjuvant (CFA)-induced thermal hyperalgesia as chronic inflammatory pain models. Administration of 5% formalin produced biphasic nociceptive behavior, and subcutaneous pretreatment with MCC950 (50 and 100 μg/50 μL), an NLRP3 inhibitor, remarkably attenuated nociceptive behavior during the second phase. Subcutaneous CFA injection induced thermal hyperalgesia 1 day after injection, which persisted for 7 days. Five days after CFA injection, subcutaneous treatment with MCC950 (50 and 100 μg/50 μL) significantly attenuated thermal hyperalgesia. Additionally, subcutaneous injection of BMS-986299 (50 and 100 μg/50 μL), an NLRP3 agonist, induced significant nociceptive behavior for 1 hour in naïve rats. Pretreatment with an interleukin-1β (IL-1β) receptor antagonist blocked the nociceptive behavior produced by subcutaneous injection of BMS-986299 (100 μg/50 μL);however, treatment with a hypoxia-inducible factor 1α inhibitor did not. These findings suggest the involvement of the peripheral NLRP3 and IL-1β pathway in chronic inflammatory pain development in the orofacial area, highlighting the potential of blocking this pathway as a strategy for developing future inflammatory pain treatment drugs.

The present study investigated the effects of QX-314 on inflammatory pain of the temporomandibular joint (TMJ). Experiments were carried out on male Sprague-Dawley rats weighing 220-280 g. Under anesthesia, the TMJ of each animal was injected with 50 microL of formalin (5%). The number of noxious behavioral responses, including rubbing or scratching of the facial region including the TMJ area, was recorded over 9 sequential 5 min intervals for each animal. Although 2.5% QX-314 did not affect formalin-induced nociceptive behavior, administration of 5% QX-314 with formalin significantly decreased the number of scratches produced by the formalin injection. Co-administration of capsaicin, a TRPV1 agonist, with 2.5% QX-314 produced significant anti-nociceptive effects whereas 2.5% QX-314 alone did not. However, the co-administration of capsaicin did not enhance the anti-nociceptive effects in the 5% QX-314-treated rats. Moreover, the co-administration of capsazepine, a TRPV1 antagonist, did not attenuate anti-nociceptive effects in the 5% QX-314-treated rats. These findings suggest that TRPV1 is effective in the transport of low but not high doses of QX-314. Moreover, a high dose of QX-314, which is not mediated by peripheral TRPV1 activity, may be viable therapeutic strategy for inflammatory pain in the TMJ.
Anesthesia ; Animals ; Capsaicin* ; Formaldehyde ; Humans ; Male ; Pain Measurement ; Rats* ; Rats, Sprague-Dawley ; Temporomandibular Joint*

The present study was to evaluate effects of vitamin E on intravenous administration of lidocaine-induced antinociception. Experiments were carried out using male Sprague-Dawley rats. Orofacial formalin-induced nociceptive behavioral responses were used as the orofacial animal pain model. Subcutaneous injection of formalin produced significant nociceptive scratching behavior. Intraperitoneal injection of 5 and 10 mg/kg of lidocaine attenuated formalin-induced nociceptive behavior in the 2nd phase, compared to the vehicle-treated group. Intraperitoneal injection of 1 g/kg of vitamin E also attenuated the formalin-induced nociceptive behavior in the 2nd phase, compared to the vehicle-treated group. However, low dose of vitamin E (0.5 g/kg) did not affect the nociceptive behavioral responses produced by subcutaneous injection of formalin. The present study also investigated effects of intraperitoneal injection of both vitamin E and lidocaine on orofacial formalin-induced behavioral responses. Vehicle treatment affected neither formalin-induced behavioral responses nor lidocaine-induced antinociceptive effects. However, intraperitoneal injection of 0.5 g/kg of vitamin E enhanced the lidocaine-induced antinociceptive effects in the 2nd phase compared to the vehicle-treated group. Intraperitoneal injection of naloxone, an opioid receptor antagonist, did not affect antinociception produced by intraperitoneal injections of both vitamin E and lidocaine. These results suggest that treatment with vitamin E enhances the systemic treatment with lidocaine-induced antinociception and reduces side effects when systemically treated with lidocaine. Therefore, the combined treatment with vitamin E and lidocaine is a potential therapeutic for chronic orofacial pain.
Administration, Intravenous ; Animals ; Facial Pain ; Formaldehyde ; Humans ; Injections, Intraperitoneal ; Injections, Subcutaneous ; Lidocaine* ; Male ; Naloxone ; Rats* ; Rats, Sprague-Dawley ; Receptors, Opioid ; Vitamin E* ; Vitamins*

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 microL) and complete Freund's adjuvant (CFA, 25 microL) was applied subcutaneously to the vibrissa pad to produce inflammatory pain. TNP-ATP, a P2X(2,2/3,4) receptor antagonist, or OX-ATP, a P2X(7) 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 microg) significantly suppressed the number of scratches in the second phase produced by formalin injection. The subcutaneous injection of 50 microg 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 microg) and OX-ATP (100 microg) 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.
Adenosine Triphosphate ; Animals ; Formaldehyde ; Freund's Adjuvant ; Humans ; Hypersensitivity ; Injections, Subcutaneous ; Male ; Nociception ; Rats ; Rats, Sprague-Dawley

The present study investigated the role of spinal glutamate recycling in the development of orofacial inflammatory pain or trigeminal neuropathic pain. Experiments were carried out on male Sprague-Dawley rats weighing between 230 and 280 g. Under anesthesia, a polyethylene tube was implanted in the atlanto-occipital membrane for intracisternal administration. IL-1β-induced inflammation was employed as an orofacial acute inflammatory pain model. IL-1β (10 ng) was injected subcutaneously into one vibrissal pad. We used the trigeminal neuropathic pain animal model produced by chronic constriction injury of the infraorbital nerve. DL-threo-β -benzyloxyaspartate (TBOA) or methionine sulfoximine (MSO) was administered intracisternally to block the spinal glutamate transporter and the glutamine synthetase activity in astroglia. Intracisternal administration of TBOA produced mechanical allodynia in naïve rats, but it significantly attenuated mechanical allodynia in rats with interleukin (IL)-1 β-induced inflammatory pain or trigeminal neuropathic pain. In contrast, intracisternal injection of MSO produced anti-allodynic effects in rats treated with IL-1β or with infraorbital nerve injury. Intracisternal administration of MSO did not produce mechanical allodynia in naive rats. These results suggest that blockade of glutamate recycling induced pro-nociception in naïve rats, but it paradoxically resulted in anti-nociception in rats experiencing inflammatory or neuropathic pain. Moreover, blockade of glutamate reuptake could represent a new therapeutic target for the treatment of chronic pain conditions.
Amino Acid Transport System X-AG ; Anesthesia ; Animals ; Astrocytes ; Chronic Pain ; Constriction ; Glutamate-Ammonia Ligase ; Glutamic Acid* ; Humans ; Hyperalgesia ; Inflammation ; Interleukins ; Male ; Membranes ; Methionine Sulfoximine ; Models, Animal ; Neuralgia* ; Polyethylene ; Rats* ; Rats, Sprague-Dawley ; Recycling*

The present study investigated the role of central GABA(A) and GABA(B) 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 GABA(A) receptor antagonist, produced mechanical allodynia in naive rats, but not thermal hyperalgesia. However, CGP35348, a GABA(B) receptor antagonist, did not show any pain behavior in naive rats. Intracisternal administration of muscimol, a GABA(A) 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 GABA(B) receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. In contrast to GABA(A) receptor antagonist, intracisternal administration of CGP35348 did not affect either the thermal hyperalgesia or mechanical allodynia. Our current findings suggest that the GABA(A) receptor, but not the GABA(B) receptor, participates in pain processing under normal conditions. Intracisternal administration of GABA(A) receptor antagonist, but not GABA(B) 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 GABA(A) receptor provides new therapeutic targets for the treatment of chronic pain.
Anesthesia ; Animals ; Baclofen ; Bicuculline ; Catheterization ; Catheters ; Chronic Pain ; Facial Pain ; Freund's Adjuvant ; gamma-Aminobutyric Acid* ; Hyperalgesia ; Ketamine ; Mandibular Nerve ; Muscimol ; Nociception* ; Rats* ; Rats, Sprague-Dawley ; Receptors, GABA* ; Receptors, GABA-A

We investigated the role of central P2X receptors in inflammatory pain transmission in the orofacial area in rats. Experiments were carried out using male Sprague-Dawley rats weighing 230-280g. Complete Freund's adjuvant (CFA, 40 microL) was applied subcutaneously to the vibrissa pad to produce inflammatory pain. The intracisternal administration of iso-PPADS tetrasodium salt, a non-selective P2X receptor antagonist, A317491 sodium salt hydrate, a P2X2/3 receptor antagonist, 5-BDBD, a P2X4 receptor antagonist, or A438079 hydrochloride, a P2X7 receptor antagonist, was performed 5 days after CFA injection. Subcutaneous injections of CFA produced increases in thermal hypersensitivity. Intracisternal injections of iso-PPADS (25 microg) or A438079 (25 or 50 microg) produced significant anti-hyperalgesic effects against thermal stimuli compared to the vehicle group. A317491 or 5-BDBD did not affect the head withdrawal latency times in rats showing an inflammatory response. Subcutaneous injections of CFA resulted in the up-regulation of OX-42, a microglia marker, and GFAP, an astrocyte marker, in the medullary dorsal horn. The intracisternal administration of A438079 reduced the numbers of activated microglia and astrocytes in the medullary dorsal horn. These results suggest that a blockade of the central P2X7 receptor produces antinociceptive effects, mediated by inhibition of glial cell function in the medullary dorsal horn. These data also indicate that central P2X7 receptors are potential targets for future therapeutic approaches to inflammatory pain in the orofacial area.
Animals ; Astrocytes ; Freund's Adjuvant ; Head ; Horns ; Humans ; Hyperalgesia ; Hypersensitivity ; Inflammation ; Injections, Subcutaneous ; Male ; Microglia ; Neuroglia ; Rats* ; Rats, Sprague-Dawley ; Receptors, Purinergic P2X4 ; Receptors, Purinergic P2X7* ; Sodium ; Up-Regulation