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.

Characterization of succinic semialdehyde dehydrogenase from Aspergillus niger.

The catabolism of fungal 4-aminobutyrate (GABA) occurs via succinic semialdehyde (SSA). Succinic semialdehyde dehydrogenase (SSADH) from the acidogenic fungus Aspergillus niger was purified from GABA grown mycelia to the highest specific activity of 277 nmol min-1 mg-1, using phenyl Sepharose and DEAE Sephacel chromatography. The purified enzyme was specific for its substrates SSA and NAD+. The substrate inhibition observed with SSA was uncompetitive with respect to NAD+. While product inhibition by succinate was not observed, NADH inhibited the enzyme competitively with respect to NAD+ and noncompetitively with respect to SSA. Dead-end inhibition by AMP and p-hydroxybenzaldehyde (pHB) was analyzed. The pHB inhibition was competitive with SSA and uncompetitive with NAD+; AMP competed with NAD+. Consistent with the kinetic data, a sequential, ordered Bi Bi mechanism is proposed for this enzyme.

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.

GABA-induced inactivation of Cebus apella V2 neurons: effects on orientation tuning and direction selectivity

We investigated the GABA-induced inactivation of V2 neurons and terminals on the receptive field properties of this area in an anesthetized and paralyzed Cebus apella monkey. Extracellular single-unit activity was recorded using tungsten microelectrodes in a monkey before and after pressure-injection of a 0.25 or 0.5 M GABA solution. The visual stimulus consisted of a bar moving in 8 possible directions. In total, 24 V2 neurons were studied before and after blocker injections in 4 experimental sessions following GABA injection into area V2. A group of 10 neurons were studied over a short period. An additional 6 neurons were investigated over a long period after the GABA injection. A third group of 8 neurons were studied over a very long period. Overall, these 24 neurons displayed an early (1-20 min) significant general decrease in excitability with concomitant changes in orientation or direction selectivity. GABA inactivation in area V2 produced robust inhibition in 80% and a significant change in directional selectivity in 60% of the neurons examined. These GABA projections are capable of modulating not only levels of spontaneous and driven activity of V2 neurons but also receptive field properties such as direction selectivity.

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.

Pregabalin in muscular cramps [charely hoarse] a new application

Pregabalin is a newly introduced medicine which is an analogue to Gaba pentin and similar to its structure, it was approved by the FDA in 2004 and marketed by Pfizer company under the name of LARYICA. It has been described in various medical disorders among which are: neuropathic pain as that of diabetes [1,2], post herpetic neuralgia [3], seizure disorders [4] and anxiety state [5]. Pregabalin the first medicine approved for treatment of fibromyalgia by the FDA [6,7] Pharmacologically Pregabalin bind to alpha 2 delta subunit of the voltage-dependent calcium channels in the central nervous system, it also decrease the releases neurotransmitters such as glutamate, noradrenalin and the substance P [8,9]. Though FDA label indications are; diabetic peripheral neuropathy, fibromyalgia, Post herpetic neuralgia and as an adjunct in seizure, yet Pregabalin have been Used in many other conditions on empirical bases as a treatment of a single case Or more as in post operative Pain [10] or hot flash [11] beside other diseases. Herewith I am reporting an unusual clinical observation never been described before, the Night Muscular cramps in the Legs collegially known as "Charley hoarse" known by Iraqis as "ABU SLSHERGATE"

Evaluation of antinociceptive effect of pregabalin in mice and its combination with tramadol using tail flick test

The development of combination therapy is a coherent approach in severe pain treatment. The present study investigated the antinociceptive effect of pregabalin alone and in combination with tramadol in acute pain modeling. Therefore, three groups of male mice received either pregabalin [1 to 400 mg/Kg], tramadol [10 to 80 mg/Kg] or their combination intraperitoneally. Then latency time, maximum possible effect [%MPE] and area under curve [AUC] were calculated in tail flick test. The antinociceptive indexes were significantly increased in10, 100 and 200 mg/kg of pregabalin while tramadol showed dose-dependent antinociception [effective dose 50% was 54 to 79 mg/Kg]. The antinociceptive effect of 100 mg/Kg of pregabalin [%MPE = 35 +/- 4%] was similar to that of 50 mg/Kg of tramadol. The combination of non-analgesic doses [10 mg/Kg] of tramadol and pregabalin did not increase%MPE and AUC, but the co-administration of 30 mg/Kg of tramadol with pregabalin [10 mg/Kg] increased all antinociceptive indexes significantly compared to the controls and with each drug alone. In conclusion, pregabalin showed a comparable antinociceptive effect to tramadol. The increase in analgesic effect was observed after the combination of low analgesic doses of tramadol with pregabalin, while the combination of non-analgesic doses of each drug reversed the interaction to antagonism. Therefore to increase the analgesic effect in pain management, more attention should be paid to respecting right proportion of drug combination. Further studies that specify the mechanism[s] and statement of interaction are needed to expand these findings to clinical applications

Attenuation of hemodynamic responses following laryngoscopy and tracheal intubation

The present study was conducted to compare the effect of clonidine and gabapentin premedication in modifying the hyperdynamic response following laryngoscopy and tracheal intubation. Seventy-five ASA I-II patients of both sexes [37 males [49.3%], 38 females [50.7%]] 18 to 45 years [mean 32.8 +/- 8.65yr.] were randomly allocated into three equal groups [25 each]. Group-1 received 0.2 mg clonidine, Group-2 received placebo and Group-3 received 900 mg gabapentin, 120 minute before operation. Heart rate, systolic, diastolic and mean arterial blood pressure were measured before induction of anesthesia, before laryngoscopy, and 1, 3, 5, 10 min after intubation. Analysis revealed that the heart rate, systolic, diastolic and mean arterial blood pressure significantly differed between groups [p < 0.001, p = 0.003, p < 0.001, p < 0.001, respectively]. The highest rates of heart rate, systolic, diastolic and mean arterial blood pressure were in the placebo group and in one minute after laryngoscopy, and the lowest rate were in the gabapentin group at the time of 1, 3, 5 and 10 after laryngoscopy, except that the lowest rate of heart rate in 10 min after laryngoscopy was in clonidine group. The data propose that both clonidine and gabapentin have effective role in blunting hyperdynamic responses after laryngoscopy, more so with gabapentin

[Comparison of the effects of preemptive gabapentin and dextromethorphan on the postoperative pain after open prostatectomy]

Preemptive administration of gabapentin and dextromethorphan has been shown to be effective for reduction of postoperative pain; but the effect of these two drugs has not yet been compared. The aim of the present study was to compare the effects of administration of gabapentin and dextromethorphan on the postoperative pain after open prostatectomy. In a randomized clinical trial, 80 adult males with ASA class of I, II and III who were candidate for open prostatectomy under spinal anesthesia in Shahid Hasheminejad Educational Center [in Tehran] were enrolled and randomly allocated to two groups of gabapentin [n=40] and dextromethorphan [n=40]. In dextromethorphan group, 60 mg of dextromethorphan syrup and in gabapentin group, 300 mg of gabapentin syrup were administered 2 hours preoperatively. During operation, the maximum height of block was determined at 5, 10 and 15 minutes after spinal anesthesia establishment. In postoperative period, at 1, 2, 12, and 24 hours, the pain intensity was measured through Visual Analogue Pain Scale [VAS]; and, overall opioid consumption and the time to first analgesic request were recorded as well. While the pain intensity in all the measurements was comparable between groups, at the 2nd hour, the pain was significantly lesser in gabapentin group [2.70 +/- 1.51 vs. 3.74 +/- 1.77, P=0.006]. Also, the time for the first analgesic request was comparable between study groups; however, the total dose of postoperative opioid consumption was lesser in gabapentin group [45.0 +/- 39.32 vs. 64.45 +/- 32.12 mg, P=0.018]. Moreover, the height of block showed no significant difference. Preemptive oral administration of 300 mg of gabapentin syrup in patients undergoing open prostatectomy under spinal anesthesia significantly lessens the pain intensity and the total dose of opioid consumption compared with 60 mg of dextromethorphan syrup. Meanwhile, the level of spinal anesthesia and the time for the first analgesic request were comparable between groups

Role of the caudal pressor area in the regulation of sympathetic vasomotor tone

It is well known that the ventrolateral medulla contains neurons involved in the tonic and reflex control of the cardiovascular system. Two regions within the ventrolateral medulla were initially identified: the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Activation of the RVLM raises arterial blood pressure and sympathetic nerve activity, and activation of the CVLM causes opposite effects. The RVLM premotor neurons project directly to sympathetic preganglionic neurons and are involved in the maintenance of resting sympathetic vasomotor tone. A significant proportion of tonic activity in the RVLM sympathetic premotor neurons is driven by neurons located in a third region of the ventrolateral medulla denominated caudal pressor area (CPA). The CPA is a pressor region located at the extreme caudal part of the ventrolateral medulla that appears to have an important role controlling the activity of RVLM neurons. In this brief review, we will address the importance of the ventrolateral medulla neurons for the generation of resting sympathetic tone related to arterial blood pressure control focusing on two regions, the RVLM and the CPA.

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.

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.

Gabapentina: farmacologia, uso clinico e interacoes farmacologicas / Gabapentin: pharmacology, clinical indication and pharmacological interactions

A gabapentina e uma nova substancia analoga ao acido gama-aminoburitico (GABA). Tem-se demonstrado efetiva como terapia adjuvante em convulsoes parciais e no tratamento de algumas neuralgias, assim como em algumas afeccoes psiquiatricas. Possui a vantagem de nao ter metabolismo hepatico, nao se ligar a proteinas plasmaticas, possui poucos efeitos adversos e potencial muito baixo para interacoes medicamentosas.

Effects of GABA on pancreatic exocrine secretion of rats

Since GABA and its related enzymes had been determined in beta-cells of pancreas islets, effects of GABA on pancreatic exocrine secretion were investigated in the isolated perfused rat pancreas. GABA, given intra-arterially at concentrations of 3, 10, 30 and 100 microM, did not exert any influence on spontaneous or secretin (12 pM)-induced pancreatic exocrine secretion. However, GABA further elevated cholecystokinin (10 pM)-, gastrin-releasing peptide (100 pM)- or electrical field stimulation-induced pancreatic secretions of fluid and amylase, dose-dependently. The GABA-enhanced CCK-induced pancreatic secretions were completely blocked by bicuculline (10 microM), a GABAA receptor antagonist but not affected by saclofen (10 microM), a GABA(B) receptor antagonist. The enhancing effects of GABA (30 microM) on CCK-induced pancreatic secretions were not changed by tetrodotoxin (1 microM) but partially reduced by cyclo-(7-aminoheptanonyl-Phe-D-Trp-Lys-Thr[BZL]) (10 microM), a somatostatin antagonist. In conclusion, GABA enhances pancreatic exocrine secretion induced by secretagogues, which stimulate enzyme secretion predominantly, via GABA(A) receptors in the rat pancreas. The enhancing effect of GABA is partially mediated by inhibition of islet somatostatin release. GABA does not modify the activity of intrapancreatic neurons.

Central modulation of formalin-induced acute peripheral inflammation & pain by some putative amino acid neurotransmitters in rats.

Possible central modulation of acute peripheral inflammation by putative amino acid neurotransmitters was investigated in rats by adopting formalin induced pedal inflammation as an experimental model. Out of five amino acids (GABA, glycine, DL-alanine, L-glutamic acid and L-aspartic acid) tested, intracerebroventricular (icv) administration of GABA and L-aspartic acid produced significant alteration in acute inflammation. GABA showed a significant attenuation of paw oedema and nociception whereas, L-aspartic acid produced significant increase in oedema volume along with marked hyperalgesia. In conclusion, the study confirms that CNS is capable of modulating peripheral inflammation.

Effect of GABA and baclofen on gastric mucosal protective factors.

GABA and baclofen (BAC), a GABA-mimetic agent, were investigated for antiulcerogenic activity. Orally administered GABA (100 mg/kg) and BAC (10 mg/kg) showed significant ulcer protection when given either alone for one day or for 4 days, or when given together with aspirin (ASP; 200 mg/kg x 3 days) in their 4 days treatment time in pylorus-ligated rats. Both the drugs showed a tendency to increase acid and decrease peptic output, and increased gastric mucus secretion in terms of total carbohydrate to protein ratio (TC:P) in both the above treatment groups. ASP tended to decrease acid and increase peptic output and significantly decreased TC:P ratio. Both GABA and BAC tended to reverse aspirin-induced effects, though they had little per se effect on TC:P ratio of gastric mucosal glycoproteins except an increase in sialic acid content both after one day or four days treatment. No, per se, effect on cell shedding (DNA and protein content of gastric juice) or cell proliferation (DNA/mg protein) was noted with GABA or BAC but the enhanced cell shedding induced by ASP was attenuated by them. ASP was found to enhance cell proliferation. However, neither of drug showed any effect on cell proliferation when given either alone or in combination with ASP. The antiulcerogenic effect of GABA and BAC may be due to their predominant effects on mucosal defensive factors like enhanced mucin secretion and decreased cell shedding or mucosal damage.

The role of nitric oxide (NO) in control of hypothalamic-pituitary function

Neurons containing neural nitric oxide synthase (nNOS) are found in various locations in the hypothalamus and, in particular, in the paraventricular and supraoptic nuclei with axons which project to the median eminence and extend into the neural lobe where the highest concentrations of NOS are found in the rat. Furthermore, nNOS is also located in folliculostellate cells and LH gonadotropes in the anterior pituitary gland. To define the role of NO in the release of hypothalamic peptides and pituitary hormones, we inected an inhibitor of NOS, Ng- monomethyl-L-arginine (NMMA) or a releasor of NO, nitroprusside (NP) into the third ventricle (3V) of conscious castrate rats and determined the effect on the release of various pituitary hormones. In vitro, we incubated medial basal hypothalamic (MBH) fragments and studied inhibitors of NO synthase and also releasors of NO. The results indicate that NOergic neurons play an important role in stimulating the release of corticotrophin-releasing hormone (CRH), luteinizing hormone releasing-hormone (LHRH), prolactin-RH's, particularly oxytocin, growth hormone-RH (GHRH) and somatostatin, but not FSH-releasing factor from the hypothalamus. NO stimulates the release of LHRH, which induces sexual behavior, and causes release of LH from the pituitary gland. The intrahypothalamic pathway by which NO controls LHRH release is as follows: glutamergic neurons synapse with noradrenergic terminals in the MBH which release nonepinephrine (NE) that acts on alpha1 receptors on the NOergic neuron to increase intracellular free Ca++ which combines with calmodulin to activate NOS. The NOS diffuses to the LHRH terminal and activates guanylate cyclase (GC), cyclooxygenase and lipoxygenase causing release of LHRH via release of cyclic GMP, PGE2 and leukotrienes, respectively. Alcohol and cytokines can block LHRH release by blocking the activation of cyclooxygenase and lipoxygenase without interfering with the activation of GC. GABA also blocks the response of the LHRH neurons to NO and recent experiments indicate that granulocyte macrophage colony-stimulating factor (GMCSF) blocks the response of the LHRH neuron to NP by activation of GABA neurons since the blockase can be reversed by the competitive inhibitor of GABAa receptors, bicuculine.

Anti-ulcerogenic activity of GABA and GABA mimetic agents in rats.

To elucidate the involvement of peripheral gamma- aminobutyric acid (GABA) and some GABA-mimetic agents in different models of gastric and duodenal ulcerations in rats and guinea pigs, effects of GABA, baclofen (GABAB agonist), diazepam, gamma-butyrolactone (GABA receptor agonist), sodium valproate, isoniazid (GABA-T inhibitor) and glycine (an inhibitory neurotransmitter), given po or ip were studied. All the drugs significantly reduced the ulcer index, incidence and number of ulcer in various models of gastric ulcers except glycine which failed to protect in reserpine-induced ulcers in rats. None of the drugs, except diazepam, had any protective effect on histamine-induced gastric ulcers in guinea pigs. Similarly, no protection was observed by any drug against cysteamine-induced duodenal ulcers in rats, while sodium valproate, isoniazid and glycine significantly decreased number of ulcers against histamine-induced duodenal ulcer in guinea pigs. The results suggest that GABA and GABA-mimetic agents, and glycine, an inhibitory neurotransmitter, afforded protection against some experimental models of peptic ulcer in rats. The effects appear to be due to their inhibitory effect on mucosal defensive factors.