piperidines and Facial-Pain

Current therapeutics are not effective for orofacial neuropathic pain, and better options are needed. The present study used inferior orbital nerve (ION)-injured mice to investigate the effect of inhibiting monoacylglycerol lipase (MAGL), an enzyme that degrades the major endocannabinoid 2-arachydonoylgycerol (2-AG) in orofacial neuropathic pain. The head-withdrawal threshold to mechanical stimulation of the whisker pad was reduced on days 3, 5, and 7 after ION injury. Injection of JZL184, a selective inhibitor of MAGL, on day 7 after ION injury attenuated the reduction in head-withdrawal threshold at 2 h after administration. Moreover, the numbers of MAGL-immunoreactive neurons in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were significantly greater in ION-injured mice than in sham-operated mice but were reduced after administration of JZL184. The increase in MAGL immunoreactivity suggests that increased 2-AG production is followed by rapid enzymatic degradation of 2-AG. JZL184 inhibited this degradation and thus increased 2-AG concentration in the brain, particularly in the Vc and C1-C2 regions, thus attenuating pain. Our findings suggest that inhibition of 2-AG degradation by MAGL inhibitors is a promising therapeutic option for treatment of orofacial neuropathic pain.

Topics: Animals; Arachidonic Acids; Behavior, Animal; Benzodioxoles; Endocannabinoids; Enzyme Inhibitors; Facial Pain; Glycerides; Male; Mice, Inbred C57BL; Monoacylglycerol Lipases; Neuralgia; Piperidines; Trigeminal Nerve Injuries

This study was conducted with the aim of evaluating whether electroacupuncture (EA) at acupoint St36 could produce antinociception through the activation of an endocannabinoid mechanism.. Male Wistar rats were divided into experimental groups. Heat was applied to the faces of rats, and the latency to withdraw the face was measured. Furthermore, the influence of electrical stimulation (100HzP) of acupoint St36, at a 0.5mA intensity, was investigated in the facial withdrawal threshold.. The EA produced antinociception, which lasted for 180min. This effect was antagonized by the pre-injection of AM 251, a CB. This study demonstrated for the first time that the CB1 cannabinoid receptor participates in the antinociceptive effect induced by EA.

Topics: Acupuncture Points; Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Electroacupuncture; Endocannabinoids; Facial Pain; Indoles; Male; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Wistar

The present study investigated the role of the peripheral NR2 subunits of N-methyl-d-aspartatic acid (NMDA) receptors in inflammatory orofacial pain. Experiments were carried out using adult male Sprague-Dawley rats weighing 220 to 280 g. Formalin (5%, 50 μl) was applied subcutaneously to the vibrissa pad. For each animal, the number of noxious behavioral responses, including rubbing or scratching of the facial region proximal to the injection site, was recorded for 9 sequential 5 min intervals. NR2 subunit antagonists were injected subcutaneously at 20 min prior to formalin injection. The subcutaneous injection of 100 or 200 μg of memantine significantly suppressed the number of scratches in the second phase of the behavioral responses to formalin. The subcutaneous injection of 0.25, 2.5, or 25 μg of 5,7-dichlorokynurenic acid also produced significant antinociceptive effects in the second phase. The subcutaneous injection of AP-5 at high dose produced significant antinociceptive effects in the second phase. The subcutaneous injection of PPPA and Ro 25-6981 both significantly suppressed the number of scratches in the second phase. The antinociceptive doses of memantine (200 μg), 5,7-dichlorokynurenic acid (25 μg), AP-5 (20 μg), PPPA (2.5 μg), or Ro 25-6981 (50 μg) injected into the contralateral hind paw did not affect the number of scratches in both the first and second phases. Moreover, the peripheral administration of NR2 subunit antagonists, including other NMDA receptor blockers, did not produce any motor dysfunction. These results indicate that a targeted blockade of peripheral NR2 receptors is a potentially important new method of treating inflammatory pain in the orofacial area.

Topics: Animals; Behavior, Animal; Excitatory Amino Acid Antagonists; Facial Pain; Injections; Kynurenic Acid; Male; Memantine; Pain Measurement; Phenols; Piperidines; Postural Balance; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Vibrissae

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is not always adequately resolved. Cannabinoids have demonstrated their analgesic effect in several pain conditions, both in animal models and in clinical situations. The aim of the present study was to evaluate the cannabinoid-mediated antinociception in two inflammatory models of orofacial pain (orofacial and temporomandibular joint (TMJ) formalin test) and to compare it with a spinal inflammatory model (paw formalin test). WIN 55,212-2 (0.5, 1mg/kg), a synthetic cannabinoid agonist, was intraperitoneally (i.p.) administered prior to formalin and significantly reduced the nociceptive behavioural responses in these inflammatory tests. To elucidate which subtype of receptor could be involved in such effect, two selective cannabinoid antagonists were administered prior to WIN. SR141716A (1mg/kg i.p.), the CB1 receptor-selective antagonist, was able to prevent the cannabinoid-induced analgesia in all three models, whereas SR144528 (1mg/kg i.p.), the CB2 receptor-selective antagonist, only prevented it in the paw formalin test. A comparison with the antinociceptive effects of morphine (2.5, 5, 10mg/kg, i.p.), indomethacin (2.5, 5mg/kg, i.p.) and ketamine (25, 50mg/kg, i.p.) was also performed. Morphine displayed a dose-dependent reduction of acute and inflammatory pain in all three models, whereas indomethacin and ketamine only attenuated inflammatory pain at the highest tested doses. These results indicate that the cannabinoid-induced antinociception in the orofacial region is mediated by activation of CB1 cannabinoid receptor. Moreover WIN was as effective as morphine and more effective than indomethacin and ketamine, in oral inflammatory pain.

Topics: Analgesics; Analgesics, Opioid; Anesthetics, Dissociative; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Benzoxazines; Camphanes; Facial Pain; Formaldehyde; Indomethacin; Inflammation; Ketamine; Male; Morphine; Morpholines; Motor Activity; Naphthalenes; Pain; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Temporomandibular Joint Disorders

To examine the antinociceptive effects of N-Methyl-D-aspartate (NMDA) receptor NR2 subunit antagonists in a rat model of the facial formalin test.. Experiments were carried out on adult male Sprague-Dawley rats weighing 220 to 280 g. Anesthetized rats were individually mounted on a stereotaxic frame and a polyethylene tube was implanted for intracisternal injection and, 72 hours later, formalin tests were performed. NMDA receptor antagonists were administered intracisternally 10 minutes prior to subcutaneous injection of 5% formalin (50 MicroL) into the vibrissal pad.. The intracisternal administration of 25, 50, or 100 Microg of memantine, an antagonist that acts at the NMDA ion channel site, significantly suppressed the number of scratches in the second phase of the behavioral responses to formalin. Intracisternal administration of a range of doses of 5,7-dichlorokynurenic acid, a glycine site antagonist, or DL-2-amino-5-phosphonopentanoate (AP-5), a nonselective NMDA site antagonist, produced significant antinociceptive effects in the second phase. Intracisternal administration of 1, 2.5, or 5 Microg of (2R,4S)-4-(3 Phosphonopropyl)-2-piperidine_carboxylic acid (PPPA), a competitive NR2A antagonist, significantly suppressed the number of scratches in the second phase, while only the highest dose of PPPA (5 Microg) significantly suppressed the number of scratches in the first phase. The antinociceptive effects of intracisternal injection of (alphaR, betaS)-alpha-(4Hydroxyphenyl)-_ methyl-4-(phenylmethyl)-1-Piperidinepropanol maleate(Ro 25-6981), a selective NR2B antagonist, were similar to those of PPPA. Injection of memantine, AP-5, Ro 25-6981, or vehicle did not result in any motor dysfunction. A low dose of PPPA (1 microg) or 5,7-dichlorokynurenic acid (2.5 microg) did not affect motor function. However, higher doses of PPPA and 5,7-dichlorokynurenic acid produced motor dysfunction.. The present results suggest that central NR2 subunits play an important role in orofacial nociceptive transmission. Moreover, this data also indicate that targeted inhibition of the NMDA receptor NR2 subunit is a potentially important new treatment approach for inflammatory pain originating in the orofacial area.

Topics: Animals; Behavior, Animal; Cisterna Magna; Disease Models, Animal; Excitatory Amino Acid Antagonists; Facial Pain; Formaldehyde; Injections; Injections, Subcutaneous; Kynurenic Acid; Male; Memantine; Motor Activity; Nociceptors; Phenols; Piperazines; Piperidines; Pruritus; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Time Factors; Vibrissae

The trigeminal nerve is comprised of three main divisions, ophthalmic, maxillary and mandibular, each providing somatosensory innervation to distinct regions of the head, face and oral cavity. Recently, a role for endothelins in nociceptive signaling in the trigeminal system has been proposed. The present study aimed to gain better insight into the participation of the endothelin system in trigeminal nociceptive transmission. Herein ET-1 and ET-3 mRNA was detected in the rats' trigeminal ganglion (TG). Fluorescent labeling of TG neurons revealed that ET(A) and ET(B) receptors are distributed along the entire TG, but ET(A) receptor expression slightly predominated within the three divisions. TRPV1 receptors were also detected throughout the entire TG, and a significant proportion of TRPV1-positive neurons (approximately 30%) co-expressed either ET(A) or ET(B) receptors. Our behavioral data showed that ET-1 (3 to 30 pmol/site) induced overt nociceptive responses after injection into the upper lip or temporomandibular joint (TMJ) and hyperalgesic actions when applied to the eye, while ET-3 and the selective ET(B) receptor agonist IRL-1620 (each at 3 to 30 pmol/site) showed only the first two effects. Injection of BQ-123, but not BQ-788 (ET(A) and ET(B) receptor antagonists, respectively, 10 nmol/site each, 30 min beforehand), into the ipsilateral upper lip abolished ET-1 induced facial grooming, but both antagonists markedly reduced the nociceptive responses induced by ET-1 injected into the TMJ. Taken together, these findings suggest that endothelins, acting through ET(A) and/or ET(B) receptors, may play an important role in mediating pain resulting from activation of most trigeminal nerve branches.

Topics: Animals; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-3; Endothelins; Eye; Facial Pain; Lip; Male; Neurons; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Sensory System Agents; Temporomandibular Joint; Trigeminal Ganglion; TRPV Cation Channels

Topics: Analgesics; Burning Mouth Syndrome; Europe; Facial Pain; Humans; Inflammation; Pain; Peripheral Nerve Injuries; Piperidines; Pyridines; Temporomandibular Joint Disorders; Trust

This study investigated the role of neurokinin 1 receptors (NK1R) in inflammatory cutaneous orofacial pain. The effects of subcutaneous and intracisternal administration of the NK1R antagonist SR140333 on the face rubbing response provoked by injection of 50 micro l of 1.5% formalin into the vibrissa pad were examined. Subcutaneous administration of SR140333 (5, 15, 30 mg/kg) induced a dose-related depressant effect on both the first and second phases of the formalin test. In contrast, intracisternal administration of SR140333 (10, 30, 60, 90 microg) produced a decrease only on the second phase with an apparent ceiling effect at approximately 50%. These data suggest that persistent nociceptive effects associated with orofacial cutaneous inflammation depend at least in part on the activation of NK1R.

Topics: Animals; Behavior, Animal; Cisterna Magna; Dose-Response Relationship, Drug; Facial Pain; Formaldehyde; Inflammation; Injections; Male; Neurokinin-1 Receptor Antagonists; Pain Measurement; Piperidines; Postural Balance; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1