Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0184567 (acute pain)
 3,962 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both gamma-aminobutyric acid (GABA)A and GABAB receptor subtypes have been implicated in spinally mediated antinociception in acute pain models. In the current study, the formalin test was used as a model of protracted nociception to examine the effect of intrathecally (i.t.) administered baclofen (GABAB agonist), muscimol (GABAA agonist) or midazolam (a benzodiazepine) on antinociception. At doses that did not affect motor function, baclofen (0.3 and 1.0 micrograms, i.t.) decreased the flinch response in a dose-dependent manner during Phase 1 and Phase 2. This effect was reversible by the GABAB-specific antagonist, CGP35348 ([P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid]). Muscimol (0.3 and 1.0 microgram i.t.) evoked a dose-dependent, bicuculline-reversible decrease in flinching during Phase 1 and Phase 2, but midazolam had no effect on either phase. No attenuation of the quiescent period between Phase 1 and Phase 2 was seen upon administration of baclofen, muscimol or midazolam. Additionally, no increase in nocifensive behavior was observed upon administration of either GABAA or GABAB antagonists alone. Therefore, our conclusions are that both GABAA and GABAB agonists are antinociceptive at the spinal cord level and that endogenous spinal GABA levels are insufficient for a GABA potentiator to act alone in an antinociceptive manner.
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PMID:Intrathecal baclofen and muscimol, but not midazolam, are antinociceptive using the rat-formalin model. 756 53

1. There is suggestive evidence that the septo-hippocampal system and the amygdala are involved in risk assessment behavior, a response to potential threat possibly related to anxiety. In addition, experimental results have been reported implicating the medial hypothalamus in coordinated escape, while the periaqueductal gray matter (PAG) and the median raphe nucleus serotonergic projection to the hippocampus seem to mediate freezing. The latter defensive behaviors are evoked by distal danger stimuli and may be viewed as manifestations of fear. Finally, there is a sound body of evidence indicating that the PAG commands primitive fight or flight reactions elicited by proximal threat, acute pain or asphyxia. These defense reactions may be related to rage and panic, respectively. In contrast, the lateral septal area and the bed nucleus of the stria terminalis have been shown to exert tonic inhibitory influence on defense. 2. Experimental evidence indicates that gamma-aminobutyric acid (GABA) tonically inhibits defensive behavior in the amygdala, hypothalamus and the PAG, an effect opposed by excitatory amino acids. Among monoamines, serotonin (5-HT) has been suggested to facilitate anxiety in the amygdala while inhibiting panic in the PAG. The role of noradrenaline in defense is less clear, although hypotheses implicating the locus coeruleus in anxiety and panic have been suggested. Among peptides, corticotropin-releasing factor (CRF) acting as a central neurotransmitter is thought to mediate behavioral and physiological effects of acute stress, while opioid peptides have been shown to inhibit defense in the amygdala and in the dorsal PAG. Finally, acetylcholine seems to facilitate defensive behavior in the hypothalamus and the PAG.
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PMID:Neuroanatomy and neurotransmitter regulation of defensive behaviors and related emotions in mammals. 791 35

Systemic administration of opiates or direct injection of opioid peptides into the periaqueductal gray (PAG) produces a profound antinociception which is thought to be associated with inhibition of neuronal activity in the PAG. This inhibitory effect has been postulated to result from opiate inhibition of GABAergic neurons in the PAG. Whether this opioid-GABAergic system is affected in acute pain state has not been investigated. The present study was thus designed to determine the effects of unilateral peripheral inflammation on ventrocaudal PAG gamma-aminobutyric acid (GABA) release in the rat using in vivo microdialysis and subsequent high pressure liquid chromatography (HPLC) analysis. Microdialysis was chosen to perform direct and dynamic studies of amino acid concentrations in the PAG in control rats and in animals subjected to acute and prolonged inflammation caused by injection of 120 microl of Complete Freund's Adjuvant (CFA) into the hind paw. GABA release was significantly decreased in the CFA treated groups both 24 h as well as 7 days post-treatment. GABA release decreased to approximately one-fourth that of the 24 h mineral oil control group. Likewise, veratridine-induced release of GABA was decreased in rats treated with CFA 7 days prior to dialysis. Systemic injection of naloxone (5 mg/kg i.p.) caused selective and significant block in the decrease of veratridine-induced release of GABA in the 24 h CFA-treated rats. Taken together with data from our previous studies, these results suggest that the decrease in veratridine-induced GABA release in this study may be due to an increase opiate inhibition of GABA resulting from the induction of acute or prolonged elevation of nociceptive input.
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PMID:Peripheral inflammation is associated with decreased veratridine-induced release of GABA in the rat ventrocaudal periaqueductal gray: microdialysis study. 1037 Oct 70

Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) has a broad anticonvulsant spectrum and is currently in clinical development for epilepsy. The compound has an opening effect on neuronal KCNQ channels. At higher concentrations an augmentation of gamma-aminobutyric acid (GABA) induced currents as well as a weak blocking effect on sodium and calcium currents were observed. The goal of this study was to characterise the activity of retigabine in models of acute and neuropathic pain and to investigate if the potassium channel opening effect of retigabine contributes to its activity. Retigabine was tested in mice and rats in the tail flick model of acute pain and in the nerve ligation model with tight ligation of the 5th spinal nerve (L5) using both thermal and tactile stimulation. While retigabine like gabapentin had almost no analgesic effect in mice it showed some analgesic effects in rats in the tail flick model. These effects could not be antagonised with linopirdine, a selective KCNQ potassium channel blocker, indicating a different mode of action for this activity. In L5-ligated rats retigabine significantly and dose-dependently elevated the pain threshold and prolonged the withdrawal latency after tactile and thermal stimulation, respectively. In the L5 ligation model with thermal stimulation retigabine 10 mg/kg p.o. was as effective as 100 mg/kg gabapentin or 10 mg/kg tramadol. The L5 model with tactile stimulation was used to test the role of the KCNQ potassium channel opening effect of retigabine. If retigabine 10 mg/kg p.o. was administered alone it was as effective as tramadol 10 mg/kg p.o. in elevating the pain threshold. Linopirdine (1 and 3 mg/kg i.p.) had nearly no influence on neuropathic pain response. If we administered both retigabine and linopirdine the effect of retigabine was abolished or diminished depending on the dose of linopirdine used.In summary, retigabine is effective in predictive models for neuropathic pain. The activity is comparable to tramadol and is present at lower doses compared with gabapentin. Since the anti-allodynic effect can be inhibited by linopirdine we can conclude that the potassium channel opening properties of retigabine are critically involved in its ability to reduce neuropathic pain response.
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PMID:The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation. 1500 38

Melatonin is a remarkable molecule with diverse physiological functions. Some of its effects are mediated by receptors while other, like cytoprotection, seem to depend on direct and indirect scavenging of free radicals not involving receptors. Among melatonin's many effects, its antinociceptive actions have attracted attention. When given orally, intraperitoneally, locally, intrathecally or through intracerebroventricular routes, melatonin exerts antinociceptive and antiallodynic actions in a variety of animal models. These effects have been demonstrated in animal models of acute pain like the tail-flick test, formalin test or endotoxin-induced hyperalgesia as well as in models of neuropathic pain like nerve ligation. Glutamate, gamma-aminobutyric acid, and particularly, opioid neurotransmission have been demonstrated to be involved in melatonin's analgesia. Results using melatonin receptor antagonists support the participation of melatonin receptors in melatonin's analgesia. However, discrepancies between the affinity of the receptors and the very high doses of melatonin needed to cause effects in vivo raise doubts about the uniqueness of that physiopathological interpretation. Indeed, melatonin could play a role in pain through several alternative mechanisms including free radicals scavenging or nitric oxide synthase inhibition. The use of melatonin analogs like the MT(1)/MT(2) agonist ramelteon, which lacks free radical scavenging activity, could be useful to unravel the mechanism of action of melatonin in analgesia. Melatonin has a promising role as an analgesic drug that could be used for alleviating pain associated with cancer, headache or surgical procedures.
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PMID:Potential use of melatonergic drugs in analgesia: mechanisms of action. 2000 25