Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery that paracetamol is metabolized to the potent TRPV1 activator N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) and that this metabolite contributes to paracetamol's antinociceptive effect in rodents via activation of TRPV1 in the central nervous system (CNS) has provided a potential strategy for developing novel analgesics. Here we validated this strategy by examining the metabolism and antinociceptive activity of the de-acetylated paracetamol metabolite 4-aminophenol and 4-hydroxy-3-methoxybenzylamine (HMBA), both of which may undergo a fatty acid amide hydrolase (FAAH)-dependent biotransformation to potent TRPV1 activators in the brain. Systemic administration of 4-aminophenol and HMBA led to a dose-dependent formation of AM404 plus N-(4-hydroxyphenyl)-9Z-octadecenamide (HPODA) and arvanil plus olvanil in the mouse brain, respectively. The order of potency of these lipid metabolites as TRPV1 activators was arvanil = olvanil>>AM404> HPODA. Both 4-aminophenol and HMBA displayed antinociceptive activity in various rodent pain tests. The formation of AM404, arvanil and olvanil, but not HPODA, and the antinociceptive effects of 4-aminophenol and HMBA were substantially reduced or disappeared in FAAH null mice. The activity of 4-aminophenol in the mouse formalin, von Frey and tail immersion tests was also lost in TRPV1 null mice. Intracerebroventricular injection of the TRPV1 blocker capsazepine eliminated the antinociceptive effects of 4-aminophenol and HMBA in the mouse formalin test. In the rat, pharmacological inhibition of FAAH, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors, and chemical deletion of bulbospinal serotonergic pathways prevented the antinociceptive action of 4-aminophenol. Thus, the pharmacological profile of 4-aminophenol was identical to that previously reported for paracetamol, supporting our suggestion that this drug metabolite contributes to paracetamol's analgesic activity via activation of bulbospinal pathways. Our findings demonstrate that it is possible to construct novel antinociceptive drugs based on fatty acid conjugation as a metabolic pathway for the generation of TRPV1 modulators in the CNS.
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PMID:Fatty acid amide hydrolase-dependent generation of antinociceptive drug metabolites acting on TRPV1 in the brain. 2394 Jun 28

Understanding mechanism of neuropathic pain is too complex and involves both peripheral and central pathophysiological phenomenon. Accordingly the treatment of neuropathic pain is also very complex and is unsatisfactory. The present review attempts to discuss the currently employed pharmacological agents for the management of neuropathic pain including anti-depressants, anti-convulsants, NMDA receptor antagonists, topical & local anesthetics, and upload analgesics. However, the existing pharmacotherapy has marginal efficacy and significant side effects. The review also gives an insight into various pharmacological agents with potential neuropathic pain attenuating properties in experimental models that include NSAIDs, corticosteroids, ion channel blockers (Ca(2+), Na(+), K(+), and TRP channel); ion exchange modulators (NCE and NHE); ion/molecule transport modulators (NKCC-1 and glycine); receptor modulators (kinin, histamine, 5-HT1A, dopamine, alpha & beta adrenergic, purinergic, excitatory amino acid, sigma, ORL1, endothelin, melanocortin, ephrin and PAR); enzyme inhibitors (cytosolic kinase, metalloproteinase, protease, vasopeptidase, D-amino acid oxidase, fatty acid amide hydrolase, aldose reductase and sorbitol dehydrogenase); other ligands (AGE, RAGEs, neuropeptides, neurotrophic factor, complement cascade, cytokine, glial cell & gap junction, nitrous oxide, growth factor, cell adhesion molecule and neuronal sprouting molecule). Moreover, some advanced therapeutic approaches such as neuronal cell transplantation, stem cell therapy, anti-sense oligonucleotide and recombinant therapy have also been dicussed.
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PMID:Drug therapy of neuropathic pain: current developments and future perspectives. 2409 49

The fatty acid amide hydrolase (FAAH) inhibitor URB597 increases anandamide, resulting in antidepressant/anxiolytic-like activity, likely via CB1 receptor-mediated modulation of serotonin (5-HT) and norepinephrine (NE) neurotransmission. However, the relative importance of the 5-HT and NE systems in these effects and on effects of URB597 on postsynaptic 5-HT receptors remain to be determined. Using behavioural and electrophysiological approaches, we assessed the effects of acute-single and repeated URB597 treatment on responses predicting antidepressant/anxiolytic activity, and on hippocampal 5-HT1A and 5-HT2A/C receptor sensitivity. Acute-single or serial URB597 treatment, compared to vehicle, reduced immobility in the forced swim test (FST), increased open arm visits in the elevated plus maze and shortened feeding latency in the novelty-suppressed feeding test (NSFT). Repeated URB597 treatment yielded more profound behavioural effects, which were associated with an increase in hippocampal brain-derived neurotrophic factor (BDNF). The 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA), but not the NE neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) prevented URB597-mediated antidepressant/anxiolytic-like response in the FST and NSFT, while DSP4 did not further affect URB597-mediated increase in raphe 5-HT neuron firing. Repeated URB597 administration decreased hippocampal pyramidal firing in response to 5-HT2A/C and 5-HT1A stimulation with 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) and 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), respectively, suggesting plastic adaptation of these receptors. The effects of acute-single and repeated URB597 administration on hippocampal cell firing in response to DOI or 8-OH-DPAT were similar in magnitude and intensity to the positive control citalopram. These data indicate that URB597 acts, either directly or indirectly, on the 5-HT system, increases hippocampal BDNF expression, and modifies 5-HT1A and 5-HT2A/C function.
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PMID:The fatty acid amide hydrolase inhibitor URB597 modulates serotonin-dependent emotional behaviour, and serotonin1A and serotonin2A/C activity in the hippocampus. 2674 70