Gabapentin Differentially Modulate c-Fos Expression in Hypothalamus and Spinal Trigeminal Nucleus in Surgical Molar Extraction

Abstract The study on the efficacy of oral analgesics reported that no single class of drug is effective in post-surgical dental pain. Pain following removal of third molar is most commonly used and widely accepted acute pain model for assessing the analgesic effect of drugs in humans. Reports demonstrated that analgesic efficacy in the human dental model is highly predictive. The high incidence of false-negative findings in analgesic investigations hinders the process of molecular discovery. Molecular mechanism of post-surgical pain is not known. More importantly, the animal model for postoperative dental pain is not well established. In an attempt to discover an effective post-surgical dental pain blocker with acceptable side effects, it is essential to elucidate the molecular mechanism of post-operative dental pain. The present study investigated mandibular molars extraction in rat as an animal model for the post-operative dental pain in central nervous system. Using c-Fos immunohistochemistry, we demonstrated that pre administration of GBP (150 mg/kg. i.p) significantly (p< 0.01) neutralized the surgical molar extraction induced c-Fos expression bilaterally in rat hypothalamus. Present results indicate that pain after surgical molar extraction might follow novel neural pathways therefore difficult to treat with existing anti-nociceptive drugs.

Resumo O estudo da eficácia relativa dos analgésicos orais relatou que nenhuma classe única de fármaco é eficaz na dor pós-cirúrgica dental. A dor após a remoção do terceiro molar é o modelo de dor aguda mais comumente usado e amplamente aceito para avaliar o efeito analgésico de drogas em seres humanos. Os relatos demonstraram que a eficácia analgésica no modelo dental humano é altamente preditiva. A alta incidência de achados falso-negativos em investigações analgésicas dificulta o processo de descoberta molecular. O mecanismo molecular da dor pós-cirúrgica não é conhecido. Mais importante ainda, o modelo animal para a dor pós-operatória não está bem estabelecido. Numa tentativa de descobrir um bloqueador de dor dental pós-cirúrgico eficaz com efeitos secundários aceitáveis, é essencial elucidar o mecanismo molecular da dor pós-operatória dental. Neste estudo investigamos a extração de molares inferiores de ratos como modelo animal para a dor pós-operatória no sistema nervoso central. Utilizando análise imunohistoquímica de c-Fos, demonstrou-se que a administração prévia de GBP (150 mg/kg i.p) significativamente (p<0,01) neutralizou a expressão c-Fos induzida por extração molar cirúrgica bilateralmente no hipotálamo de rato. Os resultados indicam que a dor após a extração molar cirúrgica pode seguir novas vias neurais, portanto, difícil tratar com as drogas anti-nociceptivas existentes.

Effect of gabapentin pretreatment on myoclonus after etomidate: a randomized, double-blind, placebo-controlled study / Efeito do pré-tratamento com gabapentina sobre a mioclonia após etomidato: um estudo randômico, duplo-cego e controlado por placebo

Abstract Aim: To evaluate the effects of three different doses of gabapentin pretreatment on the incidence and severity of myoclonic movements linked to etomidate injection. Method: One hundered patients, between 18 and 60 years of age and risk category American Society of Anesthesiologists I-II, with planned elective surgery under general anesthetic were included in the study. The patients were randomly divided into four groups and 2 h before the operation were given oral capsules of placebo (Group P, n = 25), 400 mg gabapentin (Group G400, n = 25), 800 mg gabapentin (Group G800, n = 25) or 1200 mg gabapentin (Group G1200, n = 25). Side effects before the operation were recorded. After preoxygenation for anesthesia induction 0.3 mg kg−1 etomidate was administered for 10 s. A single anesthetist with no knowledge of the study medication evaluated sedation and myoclonic movements on a scale between 0 and 3. Two minutes after induction, 2 µg kg−1 fentanyl and 0.8 mg kg−1 rocuronium were administered for tracheal intubation. Results: Demographic data were similar. Incidence and severity of myoclonus in Group G1200 and Group G800 were significantly lower than in Group P; sedation incidence and level were appreciably higher compared to Group P and Group G400. While there was no difference in the incidence of myoclonus between Group P and Group G400, the severity of myoclonus in Group G400 was lower than in the placebo group. In the two-hour period before induction other than sedation none of the side effects related to gabapentin were observed in any patient. Conclusion: Pretreatment with 800 mg and 1200 mg gabapentin 2 h before the operation increased the level of sedation and reduced the incidence and severity of myoclonic movements due to etomidate.

Resumo Objetivo: Avaliar os efeitos de três doses diferentes de gabapentina como pré-tratamento sobre a incidência e a gravidade dos movimentos mioclônicos associados à injeção de etomidato. Método: Cem pacientes, entre 18-60 anos, estado físico ASA I-II, programados para cirurgia eletiva sob anestesia geral, foram incluídos no estudo. Os pacientes foram randomicamente divididos em quatro grupos e duas horas antes da operação receberam cápsulas orais de placebo (Grupo P, n = 25), 400 mg de gabapentina (Grupo G400, n = 25), 800 mg de gabapentina (Grupo G800, n = 25) e 1.200 mg de gabapentina (Grupo G1.200, n = 25). Os efeitos colaterais antes da cirurgia foram registados. Após pré-oxigenação para a indução da anestesia, etomidate (0,3 mg.kg−1) foi administrado por 10 segundos. Um único anestesista, cego para a medicação do estudo, avaliou a sedação e os movimentos mioclônicos com uma escala de 0 a 3. Dois minutos após a indução, fentanil (2 µgr.kg−1) e rocurônio (0,8 mg.kg−1) foram administrados para a intubação traqueal. Resultados: Os dados demográficos foram semelhantes. A incidência e a gravidade da mioclonia nos grupos G1.200 e G800 foram significativamente menores do que no Grupo P; a incidência e o nível de sedação foram consideravelmente maiores comparados com o Grupo P e o Grupo G400. Enquanto não houve diferença na incidência de mioclonia entre os grupos P e G400, a gravidade da mioclonia no Grupo G400 foi menor do que no grupo placebo. No período de duas horas antes da indução, nenhum dos efeitos colaterais relacionados à gabapentina, exceto sedação, foi observado em qualquer paciente. Conclusão: O pré-tratamento com 800 mg e 1.200 mg de gabapentina duas horas antes da operação aumentou o nível de sedação e reduziu a incidência e a gravidade dos movimentos mioclônicos associados ao etomidato.

Anthropometric indicators of obesity in the prediction of high body fat in adolescents / Indicadores antropométricos de obesidade na predição de gordura corporal elevada em adolescentes

OBJECTIVE: To determine the anthropometric indicators of obesity in the prediction of high body fat in adolescents from a Brazilian State. METHODS: The study included 1,197 adolescents (15-17 years old). The following anthropometric measurements were collected: body mass (weight and height), waist circumference and skinfolds (triceps and medial calf). The anthropometric indicators analyzed were: body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR) and conicity index (C-Index). Body fat percentage, estimated by the Slaughter et al equation, was used as the reference method. Descriptive statistics, U Mann-Whitney test, and ROC curve were used for data analysis. RESULTS: Of the four anthropometric indicators studied, BMI, WHtR and WC had the largest areas under the ROC curve in relation to relative high body fat in both genders. The cutoffs for boys and girls, respectively, associated with high body fat were BMI 22.7 and 20.1kg/m², WHtR 0.43 and 0.41, WC 75.7 and 67.7cm and C-Index 1.12 and 1.06. CONCLUSIONS: Anthropometric indicators can be used in screening for identification of body fat in adolescents, because they are simple, have low cost and are non-invasive. .

OBJETIVO: Determinar os indicadores antropométricos de obesidade na predição da gordura corporal elevada em adolescentes de um estado brasileiro. MÉTODOS: O estudo incluiu 1.197 adolescentes (15-17 anos). As seguintes medidas antropométricas foram coletadas: massa corporal e estatura, perímetro da cintura e dobras cutâneas (tríceps e perna medial). Os indicadores antropométricos analisados foram: índice de massa corporal (IMC), perímetro da cintura (PC), razão cintura-estatura (RCE) e índice de conicidade (IC). A gordura corporal elevada, estimada pela equação de Slaughter et al., foi usada como método de referência. Estatística descritiva, teste U de Mann-Whitney e curva ROC foram usadas para a análise dos dados. RESULTADOS: Dos quatro indicadores antropométricos estudados, o IMC, a RCE e o PC tiveram as maiores áreas sob a curva ROC em relação à gordura corporal elevada relativa em ambos os sexos. Os pontos de corte para os rapazes e as moças, respectivamente, associados com gordura corporal elevada foram IMC 22,7 e 20,1 kg/m2, RCE 0,43 e 0,41, PC 75,7 e 67,7 cm e IC 1,12 e 1,06. CONCLUSÕES: Os indicadores antropométricos podem ser usados como ferramenta para identificação da gordura corporal em adolescentes, por serem um método simples, de baixo custo e não invasivo. .

Effect of carbamazepine and gabapentin on excitability in the trigeminal subnucleus caudalis of neonatal rats using a voltage-sensitive dye imaging technique

BACKGROUND: The antiepileptic drugs carbamazepine and gabapentin are effective in treating neuropathic pain and trigeminal neuralgia. In the present study, to analyze the effects of carbamazepine and gabapentin on neuronal excitation in the spinal trigeminal subnucleus caudalis (Sp5c) in the medulla oblongata, we recorded temporal changes in nociceptive afferent activity in the Sp5c of trigeminal nerve-attached brainstem slices of neonatal rats using a voltage-sensitive dye imaging technique. RESULTS: Electrical stimulation of the trigeminal nerve rootlet evoked changes in the fluorescence intensity of dye in the Sp5c. The optical signals were composed of two phases, a fast component with a sharp peak followed by a long-lasting component with a period of more than 500 ms. This evoked excitation was not influenced by administration of carbamazepine (10, 100 and 1,000 µM) or gabapentin (1 and 10 µM), but was increased by administration of 100 µM gabapentin. This evoked excitation was increased further in low Mg²+ (0.8 mM) conditions, and this effect of low Mg²+ concentration was antagonized by 30 µM DL-2-amino-5-phosphonopentanoic acid (AP5), a N-methyl-D-as-partate (NMDA) receptor blocker. The increased excitation in low Mg²+ conditions was also antagonized by carbamazepine (1,000 µM) and gabapentin (100 µM). CONCLUSION: Carbamazepine and gabapentin did not decrease electrically evoked excitation in the Sp5c in control conditions. Further excitation in low Mg²+ conditions was antagonized by the NMDA receptor blocker AP5. Carbamazepine and gabapentin had similar effects to AP5 on evoked excitation in the Sp5c in low Mg²+ conditions. Thus, we concluded that carbamazepine and gabapentin may act by blocking NMDA receptors in the Sp5c, which contributes to its anti-hypersensitivity in neuropathic pain.

Intrathecal Gabapentin Increases Interleukin-10 Expression and Inhibits Pro-Inflammatory Cytokine in a Rat Model of Neuropathic Pain

We examined the possible anti-inflammatory mechanisms of gabapentin in the attenuation of neuropathic pain and the interaction between the anti-allodynic effects of gabapentin and interleukin-10 (IL-10) expression in a rat model of neuropathic pain. The anti-allodynic effect of intrathecal gabapentin was examined over a 7-day period. The anti-allodynic effects of IL-10 was measured, and the effects of anti-IL-10 antibody on the gabapentin were assessed. On day 7, the concentrations of pro-inflammatory cytokines and IL-10 were measured. Gabapentin produced an anti-allodynic effect over the 7-day period, reducing the expression of pro-inflammatory cytokines but increasing the expression of IL-10 (TNF-alpha, 316.0 +/- 69.7 pg/mL vs 88.8 +/- 24.4 pg/mL; IL-1beta, 1,212.9 +/- 104.5 vs 577.4 +/- 97.1 pg/mL; IL-6, 254.0 +/- 64.8 pg/mL vs 125.5 +/- 44.1 pg/mL; IL-10, 532.1 +/- 78.7 pg/mL vs 918.9 +/- 63.1 pg/mL). The suppressive effect of gabapentin on pro-inflammatory cytokine expression was partially blocked by the anti-IL-10 antibody. Expression of pro-inflammatory cytokines was significantly attenuated by daily injections of IL-10. The anti-allodynic effects of gabapentin may be caused by upregulation of IL-10 expression in the spinal cord, which leads to inhibition of the expression of pro-inflammatory cytokines in the spinal cords.

Teratogenic effects of gabapentin on the skeletal system of balb/C mice fetuses

To evaluate the effects of gabapentin [GBP] administration on mice fetuses. This study was carried out in Birjand University of Medical Sciences during 2008. Thirty Balb/c pregnant mice were divided randomly into 3 groups: 2 experimental groups that received 25 mg/kg [I] and 50 mg/kg [II] of GBP intraperitoneally for the first 15 days of pregnancy, and a control group that received normal saline. External observations of day 18 fetuses and skeleton double staining were performed. Both experimental groups showed similar disorders that can be categorized as the following: 1] decrease of fetal body weight and increase of fetal resorption, 2] macroscopic malformations, and 3] skeletal malformations. Fetal body weights were significantly lower, and fetus resorptions were significantly higher in both treated groups compared to the control group. Macroscopic malformations included exencephaly, limbs defects, brachygnathia, vertebral column deformity, and fetuses with severe retarded growth. Skeletal malformations included delayed ossification, scoliosis, calvaria deformity, and mandibular hypoplasia. This study revealed that GBP can induce previously unreported severe malformations if it is used continuously during the implantation, neurulation, and organogenesis stages of pregnancy. Therefore, it is suggested that great caution should be exercised in using GBP during the early stages of pregnancy until further studies are performed to better understand these effects

Gabapentin attenuates acute hypoxic stress-induced behavioral alterations and oxidative damage in mice: possible involvement of GABAergic mechanism.

The effect of gabapentin has been investigated on acute hypoxic stress-induced behavioral alterations and oxidative damage in mice. Mice were subjected to hypoxia for 2 hr. Treatment with gabapentin (50 and 100 mg/kg) significantly increased ambulatory movements, exerted anti-anxiety like effect and reduced oxidative damage in mice subjected to acute hypoxic stress. Treatment with picrotoxin (1.0 mg/kg) per se had no significant effect on behavioral and biochemical parameters of stressed mice. Treatment with muscimol (0.05 mg/kg) per se significantly increased the locomotor activity of stressed mice, exerted significant anti anxiety effect and significantly reduced the oxidative damage. Further, pretreatment with picrotoxin (1.0 mg/kg) significantly blocked whereas pretreatment with muscimol (0.05 mg/kg) significantly potentiated the neuroprotective effect of gabapentin. These results suggest that gabapentin produces its neuroprotective effect in mice subjected to acute hypoxic stress through GABA(A) receptor mechanism.

[Gabapentin effect on visceral pain and its interaction with antinociceptive effect of morphine in mice]

Visceral pain is one of the most common forms of pain which requires new therapeutical drugs. The aim of this study is to investigate the inhibitory effect of gabapentin on induced abdominal contractions and to examine the effect of its co- administration with morphine. In this study, 96 mice received acetic-acid intraperitoneally after administration of saline, gabapentin [1, 5, 10, 50 and 100 mg/ kg], morphine [0.25, 0.5, 1, 3 and 5 m/g kg] or a combination of subanalgesic dose of morphine with subanalgesic and the lowest effective dose of gabapentin. In one group naloxone [5mg/kg/i.p] was injected 20 minutes prior to the injection of acetic acid. Then the number of writhes were counted for 45 minutes. Both gabapentin and morphine reduced writhing in a dose-dependent manner. The number of writhes decreased significantly by gabapentin [50 and 100/ mg/kg] and morphine [0.5, 1, 3, 5 mg/kg] comparing to the control group [P<0.001]. Also, the sub-analgesic dose of morphine [0.25mg/kg] with sub-analgesic and low effective dose of gabapentin [50mg/kg and 10mg/kg, respectively] significantly decreased the number of writhes [P<0.005]. The combination of low effective dose of gabapentin [50mg/kg] and sub-analgesic dose of morphine decreased the number of writhings by 94% as compared to the controls [P<0.005]. The antinociceptive effect of combinational administration was not reversed by naloxone [opioid antagonist]. These data demonstrated the comparable efficacy of gabapentin [50 and 100/ mg/ kg; i.p.] with 0.5mg/kg morphine in visceral pains. Also the combination of subanalgesic doses of gabapentin and morphine, which were ineffective alone, produced significant analgesic effect in writhing model of pain. Therefore, combination of low doses of morphine and gabapentin, due to lower rate of side effects, may be clinically considered as a safer treatment in the management of visceral pains

Application of Gabapentin in Thai women with menopausal syndrome.

Application of 100 mg. three times a day of Gabapentin group, 70 women to relieve menopausal syndrome with the following symptoms:Paresthesia,sweating, hot flushes in a comparative study with the amitriptyline group, 52 women 10 mg once daily. Analysis of data was done by Chi square which assumed that the Gabapentin is superior to amitripyline as accept alternative hypothesis (Ha) and other reject null hypothesis(H0) assumed both have the same action. The result of Chi square showed that the value of calculated Chi square (39.32) is higher than Table Chi square (6.63) at p < 0.01 so the authors have to accept that Ha means that Gabapentin therapy is more significantly effective than amitripyline(p < 0.01). In addition, the present study showed that the number need to treat (NNT) of Gabapentin =2.