Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low-threshold sensory pathways have been suggested to have an important role in the formation and maintenance of sensory abnormalities which are observed after peripheral nerve injury. Fos-like immunoreactive (Fos-LI) neurons are expressed in spinal cord laminae III-IV and the gracile nucleus by electrically stimulating the injured nerves at Abeta strength after sciatic nerve transection in rats. This suggests that the excitability of these neurons is increased by nerve injury. In this study, we investigated which receptors are involved in the regulation of the increased excitability in spinal and gracile nucleus neurons. The sciatic nerve of Sprague-Dawley rats (150 g) was transected 7 days before the experiment day. The rats were administered morphine, muscimol, baclofen, MK-801, CNQX, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) or clonidine i.p., and then electrically stimulated at 0.1 mA to the proximal region to the nerve injury site under urethane anesthesia. Two hours after the stimulation, Fos-LI expression was increased in the spinal cord dorsal horn and the gracile nucleus in control rats. Baclofen inhibited the Fos-LI expression both in the spinal cord and the gracile nucleus. Morphine inhibited only the Fos-LI expression in the posterior cutaneous (PC) nerve territory of laminae I-II, but not in the sciatic nerve (SC) territory, laminae III-IV nor the gracile nucleus. MK-801 had an inhibitory but complicated effect in laminae I-II and the gracile nucleus. The other drugs were not effective on Fos-LI expression. It is suggested that the GABA(B) receptor has a pivotal role in the regulation of Fos-LI expression after electrical stimulation to the injured low-threshold sensory fibers, and other receptors have little effect on the Fos-LI expression.
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PMID:Excitability of spinal cord and gracile nucleus neurons in rats with chronically injured sciatic nerve examined by c-fos expression. 1057 3

GABA(B) receptors influencing vagal pathways to the lower oesophageal sphincter and heart were investigated. In urethane-anaesthetized ferrets, the GABA(B) agonist baclofen (7 micromol kg(-1) i.v.) increased basal lower oesophageal sphincter (LOS) pressure. This was reversed by antagonism with CGP35348 (100 micromol kg(-1) i.v.). Baclofen's effect was abolished by vagotomy, suggesting a central action, yet it was ineffective when given centrally (3 - 6 nmol i.c.v.). Peripheral vagal stimulation (10 Hz, 5 s duration) caused LOS inhibition, followed by excitation, then prolonged inhibition. Bradycardia was also evoked during stimulation. Bradycardia and LOS responses were abolished after chronic supranodose vagotomy, indicating that they were due to stimulation of vagal pre-ganglionic neurones, not antidromic stimulation of afferents. Baclofen (1 - 10 micromol kg(-1)) reduced bradycardia and enhanced LOS excitation, which was also seen in animals pretreated with atropine (400 microgram kg(-1) i.v.) and guanethidine (5 mg kg(-1) i.v.), but not in those pretreated with L-NAME (100 mg kg(-1) i.v.). Effects of baclofen (7 micromol kg(-1) i.v.) on vagal stimulation-induced LOS and cardiac responses were unchanged by the GABA(B) antagonists CGP35348 or CGP36742 (up to 112 micromol kg(-1) i.v.), but were reversed by CGP62349 (ED(50) 37 nmol kg(-1) i.v.) or CGP54626 (ED(50) 100 nmol kg(-1) i.v.). Responses of isolated LOS strips to electrical stimulation, capsaicin, NK-1, NK-2 and nicotinic receptor agonists were all unaffected by baclofen (</=200 microM). We conclude that baclofen reduces vagal output at two peripheral sites: one presynaptically on pre-ganglionic neurones (CGP35348-insensitive), and another (CGP35348-sensitive) that could not be identified. This demonstrates heterogeneity of GABA(B) receptors through differential sensitivity to antagonists.
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PMID:GABA(B) receptor-mediated effects on vagal pathways to the lower oesophageal sphincter and heart. 1080 64

In the enteric nervous system, activation of neuronal GABA(A)- and GABA(B)-receptors has been shown to modulate neuronal activity. The consequences of this modulation depend on the location in the gastrointestinal tract or the animal species studied. These data illustrate the complexity of GABA-induced effects. Furthermore, the GABA(C)-receptor has been identified in a neuroendocrine cell line suggesting a modulating role of this third type of GABA receptor in intestinal functions. Therefore, the modulating role of GABA-receptor agonists was determined in circular preparations of rat distal colon during electrical nerve stimulation (NS) in vitro. Mechanical response to NS was characterized by a relaxation followed at the end of the stimulation by an off-contraction. In normal Krebs solution (basal conditions), muscimol and baclofen, respectively GABA(A)- and GABA(B)-agonists, induced a significant increase of the electrically induced off-contraction. The GABA(C) agonist, CACA, showed no significant effect on the response to NS. Excitatory effects of muscimol on the off-contraction were abolished in the presence of atropine. Furthermore, in the presence of atropine, muscimol increased the amplitude of the electrically induced relaxation; similarly the baclofen-induced increase of off-contraction amplitude was significantly lower than that observed in control conditions. Baclofen and muscimol effects on the off-contraction were abolished in the presence of hexamethonium or guanethidine. Furthermore, muscimol and baclofen did not induce any significant change on the response to NS in the presence of L-NAME and apamin together. Thus, it seems that in rat distal colon, GABA regulates significantly both excitatory (through GABA(A)- and GABA(B)-receptors) and inhibitory (through GABA(A)-receptors) neuronal activities. We also gave evidence for a possible interplay between GABAergic intrinsic neurons and adrenergic nerve terminals. Finally, it is shown for the first time the presence of the GABA vesicular transporter (VIAAT) around myenteric ganglia of rat colon.
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PMID:Functional evidence for a role of GABA receptors in modulating nerve activities of circular smooth muscle from rat colon in vitro. 1253 16

Baclofen was administered to rats systemically (intraperitoneal, i.p.) by itself or with L-NAME. Baclofen (1-7.5 mg/kg, i.p.) evoked dose-dependent hypothermia. L-NAME (50 mg/kg, i.p.) was ineffective. For combined administration, L-NAME increased the relative potency of baclofen (F=10.77, p<0.05), indicating multiplicative interaction and synergism. The present data reveal a surprising and significant interaction between nitric oxide synthase (NOS) and baclofen-induced hypothermia.
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PMID:Pronounced hypothermic synergy between systemic baclofen and NOS inhibitor. 1547 54

Our laboratory recently demonstrated that a drug combination of baclofen and L-NAME, a nonspecific nitric oxide synthase (NOS) inhibitor, evokes synergistic hypothermia in rats. These data are the first demonstration of synergy between a GABA agonist and NOS inhibitor. While the hypothermic synergy suggests a role for NOS in baclofen pharmacology, it is unclear whether the super-additive hypothermia is specific for baclofen and L-NAME or extends to drug combinations of baclofen and other NOS inhibitors. The site of action (central or peripheral) and isoforms of NOS that mediate the synergy are also unknown. Here, we confirm the hypothermic synergy with additional data and discuss potential mechanisms of the drug interaction. Baclofen (2.5, 3.5, 5 and 7.5 mg/kg, i.p.) was administered to rats by itself or with 7-nitroindazole (7-NI), a neuronal NOS inhibitor. 7-NI (10 mg/kg, i.p.) did not affect body temperature. For combined administration, 7-NI (10 mg/kg, i.p.) increased the relative potency of baclofen (F=18.9, P<0.05). The present data validate the hypothermic synergy caused by the drug combination of baclofen and L-NAME and implicate nNOS in the synergy. In a context broader than thermoregulation, NO production and transmission may play an important role in baclofen pharmacology.
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PMID:Baclofen and NOS inhibitors interact to evoke synergistic hypothermia in rats. 1613 4

The aims of the present study were to investigate, using mouse whole stomach in vitro, the effects of gamma-aminobutyric acid (GABA) and GABA receptor agonists on the spontaneous gastric tone, to examine the subtypes of GABA receptors involved in the responses and to determine the possible site(s) of action. GABA induced gastric relaxation, which was antagonized by the GABA(A)-receptor antagonist, bicuculline, potentiated by phaclofen, GABA(B)-receptor antagonist, but not affected by 1,2,5,6-Tetrahydropyridin-4-yl methylphosphinic acid hydrate (TPMPA), GABA(C)-receptor antagonist. Muscimol, GABA(A)-receptor agonist, mimicked GABA effects inducing relaxation, which was significantly reduced by bicuculline, N omega-nitro-L-arginine methyl ester (L-NAME), inhibitor of NO synthase or apamin, inhibitor of small conductance Ca(2+)-dependent K(+) channels, which blocks the purinergic transmission in this preparation. It was abolished by tetrodotoxin (TTX) or l-NAME plus apamin. Baclofen, a specific GABA(B)-receptor agonist, induced an increase in the gastric tone, which was antagonized by phaclofen and abolished by TTX or atropine. Bicuculline, but not phaclofen or TPMPA, per se induced an increase in gastric tone, which was prevented by L-NAME. In conclusion, our results suggest that GABA is involved in the regulation of mouse gastric tone, through modulation of intrinsic neurons. Activation of GABA(A)-receptors mediates relaxation through neural release of NO and neurotransmitters, activating Ca(2+)-dependent K(+) channels, likely purines, while activation of GABA(B)-receptors leads to contraction through acetylcholine release.
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PMID:Functional evidence for different roles of GABAA and GABAB receptors in modulating mouse gastric tone. 2008 Jan 14

In the current study, the involvement of N-methyl-d-aspartate receptor (NMDAR) and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system in the antidepressant-like effects of baclofen was evaluated by using animal model in forced swimming test. Followed by an open field test for the evaluation of locomotor activity, the immobility time for mice in force swimming test was recorded. Only the last four min was analyzed. Administration of Baclofen (0.5 and 1mg/kg, i.p.) reduced the immobility interval in the FST. Prior administration of l-arginine (750mg/kg, i.p.,) a nitric oxide synthase substrate or sildenafil (5mg/kg, i.p.) a phosphodiesterase 5 into mice suppressed the antidepressant-like activity of baclofen (1mg/kg, i.p.).Co-treatment of 7-nitroindazole (50mg/kg, i.p.,) an inhibitor of neuronal nitric oxide synthase, L-NAME (10mg/kg, i.p.,) a non-specific inhibitor of nitric oxide synthase or MK-801 (0.05mg/kg, i.p.) an NMDA receptor antagonist with subeffective dose of baclofen (0.1mg/kg, i.p.), reduced the immobility time in the FST as compared to the drugs when used alone. Co-administrated of lower doses of MK-801 (0.01mg/kg) or l-NAME (1mg/kg) failed to effect immobility time however, simultaneous administration of these two agents in same dose with subeffective dose of baclofen (0.1mg/kg, i.p.), minimized the immobility time in the FST. Thus, our results support the role of NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant-like action of baclofen.
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PMID:The involvement of NMDA receptor/NO/cGMP pathway in the antidepressant like effects of baclofen in mouse force swimming test. 2667 25