Japanese journal of pharmacology
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Two highly selective mu-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), have been identified and postulated to be endogenous mu-opioid receptor ligands. The present minireview describes the antinociceptive properties with the tail-flick test of these two ligands given intracerebroventricularly (i.c.v.) and intrathecally (i.t.) in ICR mice. EM-1 or EM-2 given i.c.v. or i.t. dose-dependently produce antinociception. ⋯ In addition, the antinociception induced by EM-2 given i.c.v. contains another component, which is mediated by the release of Met-enkephalin acting on delta2-opioid receptors in the spinal cord. It is proposed that there are two subtypes of mu-opioid receptors,which are involved in EM-1- and EM-2-induced antinociception. One subtype of mu-opioid receptors is stimulated by EM-1, EM-2 and other mu-opioid agonists morphine and DAMGO; and another subtype of mu-opioid is sorely stimulated by EM-2 and is involved in the releases of dynorphin A(1-17) and Met-enkephalin for the production of antinociception.
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Review Comparative Study
Differential antinociceptive effects induced by intrathecally-administered endomorphin-1 and endomorphin-2 in mice.
Two highly selective mu-opioid receptor (MOP-R) agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), have been identified and postulated to be endogenous ligands for MOP-R. Experiments were designed to determine the involvement of subtypes of MOP-R on the antinociceptive effects of EM-1 or EM-2 using the paw withdrawal test. The intrathecal (i.t.) injection of EM-1 and EM-2 produced dose-dependent antinociception in mice 1 min after the injection. ⋯ EM-2-induced antinociception was attenuated by pretreatment with s.c. nor-binaltorphimine and naltrindole, whereas the effect of EM-1 was not affected. Moreover, the antinociceptive effect of EM-2 was attenuated by i.t. pretreatment with antisera against dynorphin A(1-17) or methionine-enkephalin. These results suggest that EM-2-induced antinociception may be mediated by the subtype of MOP-R, which is sensitive to NLZ and 3-MNT, and by subsequent release of dynorphin A(1-17) and methionine-enkephalin in the spinal cord.
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A variety of different isoforms of voltage-sensitive Na+ channels have now been identified. The recent three-dimensional analysis of Na+ channels has unveiled a unique and unexpected structure of the Na+ channel protein. Na+ channels can be classified into two categories on the basis of their amino acid sequence, Nav1 isoforms currently comprising nine highly homologous clones and Nax that possesses structure diverging from Nav1, especially in several critical functional motifs. ⋯ The demonstration of its dependence on Nav1.9 provides evidence for a specialized role of Nav1.9, together with Nav1.8, in pain sensation. Although Nax has not been successfully expressed in an exogenous system, recent investigations using relevant native tissues combined with gene-targeting have disclosed their unique "concentration"-sensitive but not voltage-sensitive roles. In this context, these emerging views of novel functions mediated by different types of Na+ channels are reviewed, to give a perspective for future research on the expanding family of Na+ channel clones.
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Malignant hyperthermia (MH) is a pharmacogenetical complication of general anesthesia resulting from abnormal Ca2+-induced Ca2+ release (CICR) via the type 1 ryanodine receptor (RyR1) in skeletal muscles. In this study, we analyzed the genomic DNAs prepared for determination of all the 106 exons of the RyR1 gene from blood samples donated by two MH patients with extremely high CICR rates in their biopsied skeletal muscles and a clear history of MH incidence. Two novel point mutations were found in the exons 96 and 101 with alterations in the coded amino acids within the C-terminal channel region, i.e., Pro4668 to Ser and Leu4838 to Val. ⋯ It was found that the L to V but not the P to S mutation of the RyR1 resulted in enhanced Ca2+ release activity. These results indicate that the L4838V mutation is responsible for the MH incidence. The L4838V mutation is unique because it is the mutation first found within a hydrophobic transmembrane segment of the channel region and should provide further information on the function of the RyR1 as well as for genetic diagnosis of MH.
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Using the cannula inserting method, vasoconstrictor responses to alpha1-adrenoceptor agonists (noradrenaline [NA], phenylephrine [PE] and methoxamine [ME]) and effects of alpha1-adrenoceptor antagonists (WB4101, chloroethylclonidine [CEC] and BMY7378) were investigated in isolated and perfused rat common carotid arteries. The rank order of agonist potency and efficacy was NA = PE > ME. ⋯ The ME-induced responses were also significantly blocked by either WB4101 or BMY7378. From these results, it is concluded that there are functional alpha1A- and alpha1D-adrenoceptor subtypes in rat common carotid arteries, but no functional alpha1B subtype.