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Descending control of nociception (DCN), a measure of efficiency of descending pain inhibition, can be assessed in animals by the combined application of test and conditioning noxious stimuli. Evidence from pre-clinical and clinical studies indicates that this mechanism of pain control may differ between sexes and might be impaired in many chronic pain states. However, little is known about sex differences in DCN efficiency in models of acute and chronic orofacial pain. Herein, we first evaluated DCN responses in male and female rats by the applying formalin into the upper lip or capsaicin into the forepaw as the conditioning stimulus, followed by mechanical stimulation (Randall-Selitto) of the hind paw as the test stimulus. The same protocol (i.e., capsaicin in the forepaw followed by mechanical stimulation of the hind paw) was evaluated in male and female rats on day 3 after intraoral incision and on day 15 and 30 after chronic constriction injury of the infraorbital nerve (CCI-ION). Additionally, we assessed the effect of the kappa opioid receptor (KOR) antagonist Norbinaltorphimine (nor-BNI) on DCN responses of female nerve-injured rats. This study shows that naïve female rats exhibit less efficient DCN compared to males. Postoperative pain did not alter DCN responses in female and male rats, but CCI-ION induced loss of DCN responses in females but not in males. Systemic pretreatment with nor-BNI prevented the loss of DCN induced by CCI-ION in female rats. The results reveal sex differences in DCN responses and female-specific impairment of DCN following chronic orofacial pain. Moreover, the findings suggest that, at least for females, blocking KOR could be a promising therapeutic approach to prevent maladaptive changes in chronic orofacial pain.

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Trigeminal neuropathic pain (TNP) is an intense pain condition characterized by hyperalgesia and allodynia; however, its neural mechanisms are not completely understood. Its management is complex, and studies that investigate its biochemical mechanisms are important for improving clinical approaches. This study aimed to evaluate the involvement of GABAergic, glutamatergic, and opioidergic systems and brain-derived neurotrophic factor (BDNF) levels in the TNP process in rats. TNP is induced by chronic constriction injury of the infraorbital nerve (CCI-ION). Nociceptive responses were evaluated using the facial von Frey test before and after the administration of GABAergic and opioidergic agonists and glutamatergic antagonists. The rats were divided into vehicle-treated control (C), sham-surgery (SS), and CCI-ION groups, and then subdivided into the vehicle (V)-treated SS-V and CCI-ION-V groups, SS-MK801 and CCI-ION-MK801, treated with the N-methyl-d-aspartate receptor selective antagonist MK801; SS-PB and CCI-ION-PB, treated with phenobarbital; SS-BZD and CCI-ION-BZD, treated with diazepam; SS-MOR and CCI-ION-MOR, treated with morphine. BDNF levels were evaluated in the cerebral cortex, brainstem, trigeminal ganglion, infraorbital branch of the trigeminal nerve, and serum. CCI-ION induced facial mechanical hyperalgesia. Phenobarbital and morphine reversed the hyperalgesia induced by CCI-ION, and the CCI-BZD group had an increased nociceptive threshold until 60 min. CCI-ION-GLU increased the nociceptive threshold at 60 min. Cerebral cortex and brainstem BDNF levels increased in the CCI-ION and SS groups. Only the CCI group presented high levels of BDNF in the trigeminal ganglion. Our data suggest the involvement of GABAergic, glutamatergic, and opioidergic systems and peripheral BDNF in the TNP process.

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Painful post-traumatic trigeminal neuropathy (PTTN) involves spontaneous and evoked pain, of moderate to severe intensity, continuous and described as burning or shooting. The first line treatment is pharmacological. However, botulinum toxin - A (BoNT-A) can be used when medications cannot control pain. This article describes the use of BoNT-A in a case of PTTN refractory to conventional pharmacological treatment. A 44-year-old male patient presented with an 8-years history of pain in the lower left second molar region. Pain was burning, lasting for seconds, with multiple pain episodes per day. Diagnosis hypothesis was PTTN. After no improvement with conventional pharmacological treatment, injections of BoNT-A were elected. Somatosensory assessment showed a significant reduction in visual analog scale for touch, cold and pinprick sensitivity. Likewise, patient's impression of change in pain significantly improved after BoNT-A injections. Our results suggest that BoNT-A could be used as a treatment for PTTN refractory to conventional treatments. (AU)

A neuropatia trigeminal pós-traumática dolorosa (PTTN) envolve dor espontânea e evocada, de intensidade moderada a grave, contínua e descrita como queimante ou lascinante. O tratamento de primeira linha é farmacológico. No entanto, a toxina botulínica - A (BoNT-A) pode ser usada quando os medicamentos não conseguem controlar a dor. Este artigo descreve o uso da BoNT-A em um caso de PTTN refratário ao tratamento farmacológico convencional. Paciente de sexo masculino, 44 anos, com 8 anos de dor na região do segundo molar inferior esquerdo. A dor foi descrita como queimante, com duração de segundos e com vários episódios por dia. A hipótese de diagnóstico foi PTTN. Após nenhuma melhora com o tratamento farmacológico convencional, as injeções de BoNT-A foram eleitas. A avaliação somatossensorial mostrou uma redução significativa na escala visual analógica para sensibilidade ao toque, frio e picada após BoNT-A. Da mesma forma, a impressão de mudança do paciente na dor melhorou significativamente após as injeções de BoNT-A. Nossos resultados sugerem que o BoNT-A poderia ser usada como tratamento para PTTN refratário a tratamentos convencionais. (AU)

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Herein, it was investigated whether a complex of lidocaine with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) would present a better antinociceptive profile in vivo when compared with plain lidocaine in models of orofacial pain. Plain lidocaine (LDC) and complexed lidocaine (LDC:HP-ß-CD) were initially evaluated in vitro to determine the release rate of the two formulations. Subsequently, the effect of both formulations was evaluated in independent groups of rats submitted to the orofacial formalin test, induction of facial heat hyperalgesia by capsaicin and carrageenan, and induction of facial heat and mechanical hyperalgesia by constriction of the infraorbital nerve. LDC:HP-ß-CD led to a reduction in the lidocaine release assessed in the in vitro release assay compared to plain LDC. Both formulations presented an antinociceptive effect in all models, but LDC:HP-ß-CD showed a better effect in the second phase of the formalin response, in carrageenan-induced heat hyperalgesia, and in the heat hyperalgesia associated to infraorbital nerve constriction. Our results show that complexation improved in vivo antinociceptive effects of LDC, but further studies are necessary to elucidate what properties contribute to the better effect of the complexed formulation on this models and/or what characteristics of the pain model facilitate the action of the complexed formulation.

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The Chronic Constriction Injury of the Infraorbital Nerve (CCI-ION) is a well-established model to study facial sensory changes related to trigeminal neuropathic pain. CCI-ION induces heat hypersensitivity that resolves within 2-3 weeks and a delayed mechanical hypersensitivity that emerges during the second week post-injury. The role of descending facilitatory pain pathways from the rostro ventromedial medulla (RVM) in mediating the heat and tactile hypersensitivity was examined. CCI-ION induced heat hypersensitivity observed 5days post-surgery was reversed by systemic, but not RVM lidocaine. CCI-ION-induced tactile hypersensitivity observed 15days post-surgery was reversed by systemic lidocaine and attenuated by RVM lidocaine. CCI-ION-induced spontaneous pain was determined using conditioned place preference (CPP) to pain relief at each time-point. At day 5 post-CCI-ION, neither systemic nor RVM lidocaine induced CPP. However, at 15days post-CCI-ION, CPP was observed to the chamber paired with RVM lidocaine, but not systemic lidocaine. These data indicate that CCI-ION induced heat hypersensitivity is not dependent on descending facilitatory pain pathways 5-days post-injury whereas descending facilitatory pain pathways mediate tactile allodynia and spontaneous pain 15days post-CCI-ION. This suggests that CCI-ION induces early peripheral sensitization followed by development of central sensitization that mediates spontaneous pain and contributes to mechanical hypersensitivity.

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BACKGROUND: Facial chronic neuropathic pain (FCNP) is a disabling clinical entity, its incidence is increasing within the chronic pain population. There is indication for neuromodulation when conservative treatment fails. Motor cortex stimulation (MCS) has emerged as an alternative in the advanced management of these patients. The aim of this work is to review the worldwide literature on MCS for FCNP. METHODS: A PubMed search from 1990 to 2012 was conducted using established MeSH words. A total of 126 relevant articles on MCS focused on chronic pain were selected and analysed. Series of cases were divided in (1) series focused on MCS for FCNP, and (2) MCS series of FCNP mixed with other chronic pain entities. RESULTS: A total of 118 patients have been trialed for MCS for FCNP, 100 (84.7%) pursued permanent implantation of the system, and 84% of them had good pain control at the end of the study. Male: female ratio was about 1:2 in the whole group of studies; mean age was 58 years (range, 28-83), and mean pain duration was 7 years (range, 0.6-25). Four randomized controlled studies have been reported, all of them not focused on MCS for FCNP. The most common complication was seizure followed by wound infection. Preoperative evaluation, surgical techniques, and final settings varied among the series. CONCLUSION: MCS for FNCP is a safe and efficacious treatment option when previous managements have failed; however, there is still lack of strong evidence (larger randomized controlled multicentre studies) that MCS can be offered in a regular basis to FNCP patients.