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

Catechol-O-methyltransferase (COMT) has two isoforms: soluble (S-COMT), which resides in the cytoplasm, and membrane-bound (MB-MT), anchored to intracellular membranes. COMT is involved in the O-methylation of L-DOPA, dopamine and other catechols. The exact role of MB-COMT is still mostly unclear. We wanted to create a novel genetically modified mouse model that specifically lacks MB-COMT activity and to study their behavioral phenotype. MB-COMT knock-in mutant mice were generated by introducing two point mutations in exon 2 of the Comt gene (ATGCTG->GAGCTC disabling the function of the P2 promoter and allowing only the P1-regulated S-COMT transcription. The first mutation changes methionine to glutamic acid whereas the second one does not affect coding. The expression of the two COMT isoforms, total COMT activity in several areas of the brain and peripheral tissues and extracellular dopamine concentrations after L-DOPA (10 mg/kg) and carbidopa (30 mg/kg) subcutaneous administration were assessed. A battery of behavioral tests was performed to compare MB-COMT deficient mice and their wild type littermates of both sexes. MB-COMT deficient mice were seemingly normal, bred usually and had unaltered COMT activity in the brain and periphery despite a complete lack of the MB-COMT protein. MB-COMT deficient male mice showed higher extracellular dopamine levels than their wild-type littermates in the striatum, but not in the mPFC. In addition, the MB-COMT deficient male mice exhibited a distinct endophenotype characterized by schizophrenia-related behaviors like aggressive behavior and reduced prepulse inhibition. They also had prolonged immobility in the tail suspension test. Both sexes were sensitized to acute pain and had normal motor activity but disturbed short-term memory. Hence the behavioral phenotype was not limited to schizophrenia-related endophenotype and some behavioural findings were not sex-dependent. Our findings indicate that MB-COMT is critical for behavior, and its function in COMT-dependent brain areas cannot be entirely substituted by the remaining S-COMT.
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PMID:Generation of membrane-bound catechol-O-methyl transferase deficient mice with disctinct sex dependent behavioral phenotype. 2819 63

Background There are a number of false myths about buprenorphine based on unconfirmed animal data, even from isolated animal organs, and early clinical research. These myths came into textbooks on pharmacology and pain about 30 years ago and have been difficult to eradicate. Animal models of pain and pain relief are notoriously unreliable as predictors of human clinical effects. The fact is that in clinical practice there is NO bell-shaped dose-response curve, there is NO plateau on the dose-response curve, and there is NO antagonist effect from buprenorphine on other mu-opioid agonists. Methods This narrative, topical review of relevant research publications evaluates new knowledge on the pharmacodynamics and pharmacokinetics of buprenorphine of importance in clinical practice. Results Buprenorphine is a potent opioid analgesic acting on all four opioid receptors: it is an agonist on the mu-, the delta, and the ORL-1 receptors. It is an antagonist at the kappa-receptor. Buprenorphine has a number of active metabolites with different effects on the four opioid receptors; all except the norbup-3-glu are analgesic. Buprenorphine itself is not a respiratory depressant or sedative, but some of its active metabolites are. Buprenorphine and its active metabolites are not excreted by the kidney. Therefore buprenorphine may be used in patients with advanced renal failure. Buprenorphine has a slow onset and a long offset. These properties are advantageous, except sometimes when treating severe acute pain. Its agonist effect on the ORL-1 receptor reduces reward-effects and slows the development of tolerance to the analgesic effects. Buprenorphine inhibits voltage-gated sodium-channels and enhances and prolongs peripheral nerve blocks. Its ORL-1 -effect at the spinal cord may do the same. Buprenorphine is well suited for treatment of chronic pain, especially chronic neuropathic pain and cancer pain. The beneficial effects as a co-medication during treatment of the opioid-abuse disease are due to its slow onset (less "kick-effect"). Its prolonged offset-time reduces the likelihood of acute withdrawal problems and reduces the "craving" of opioids. Adverse effects Buprenorphine, being a mu-agonist, may induce or maintain opioid addiction. Illegally obtained high-dose transmucosal buprenorphine, intended for treatment of addiction, is dissolved and injected by opioid abusers. This is an increasing problem in some countries. Conclusions Buprenorphine's unusual pharmacodynamics and pharmacokinetics make it an ideal opioid for treatment of most chronic pain conditions where opioid therapy is indicated. Implications Buprenorphine is a well studied and often misunderstood analgesic opioid drug. The evidence base predicts that it will be an increasingly important alternative for treatment of chronic pain conditions caused by cancer and non-cancer diseases. It will continue to be an attractive alternative to methadone for opioid abuse rehabilitation.
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PMID:Buprenorphine-Clinically useful but often misunderstood. 2991 11