European journal of pharmacology
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In the present study, the possible role of nitric oxide on the conditioned place preference (CPP) induced by nicotine in mice was investigated. Intraperitoneal (i.p.) injections of nicotine (1 mg/kg) and the nitric oxide (NO) precursor, L-arginine (200 and 500 mg/kg), produced significant place preference. However, injection of mecamylamine (0.05 and 0.1 mg/kg; i.p.) or the NO synthase (NOS) inhibitor, L-Nitro-amino-methyl-ester, L-NAME (5-20 mg/kg; i.p.), had no effect. ⋯ Nicotine injection (0.25, 0.5 and 0.75 mg/kg) on the test day reduced the expression of place preference induced by L-arginine, while both mecamylamine (0.05 and 0.1 mg/kg) and L-NAME (5, 10 and 20 mg/kg) inhibited the acquisition of place preference induced by nicotine (1 mg/kg) and L-arginine (200 mg/kg). Moreover, neither of the antagonists reduced the expression of nicotine- or L-arginine-induced place preference. It is suggested that nitric oxide may play an important role in nicotine-induced place preference.
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The activation of intracerebral corticotropin releasing factor (CRF) system is involved in nitrous oxide analgesia. We evaluated the effect of general anesthetics on nitrous-oxide-induced CRF activation and antinociception. Male Sprague-Dawley rats inhaled isoflurane (0%, 0.6%, 1.0% and 1.5%) or were administered with intravenous propofol (0, 0.1 and 0.2 mg/kg/min), with or without 75% nitrous oxide inhalation, for 90 min. ⋯ In other groups of rats, the effect of propofol on nitrous oxide antinociception was evaluated with tail flick latency tests. Both inhaled isoflurane and intravenous propofol inhibited nitrous-oxide-induced activation of CRF neurons, suggesting that these general anesthetics may inhibit one of the analgesic mechanisms of nitrous oxide. Indeed, propofol inhibited the antinociceptive action of nitrous oxide, as evaluated with tail flick latencies (TFL).
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Comparative Study
Roles of serotonin receptor subtypes for the antinociception of 5-HT in the spinal cord of rats.
The contribution of 5-HT (5-hydroxytryptamine) receptor subtypes to the antinociception produced by intrathecal 5-HT in the formalin test was investigated in rats. Intrathecal 5-HT suppressed both phases of behaviors produced by 5% formalin, and this was blocked by antagonists for 5-HT(1B) (3-[3-(Dimethylamino)propyl]-4-hy-droxy-N-[4-(4-pyridinyl)phenyl]benzamide dihydrochloride, GR 55562), 5-HT(2C) (N-ormethylclozapine/8-Chloro-11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine, D-MC), 5-HT3 (1-Methyl-N-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-1H-indazole-3-carboxamide maleate, LY-278,584) and 5-HT4 receptors (4-Amino-5-chloro-2-metho-xy-benzoic acid 2-(diethylamino)ethyl ester hydrochloride, SDZ-205,557), but not the 5-HT(1D) receptor antagonist 3-[4-(4-Chlorophenyl)piperazin-1-yl]-1,1-diphenyl-2-propanol hydrochloride (BRL 15572). ⋯ The results of the present study indicate that spinal 5-HT(1B,) 5-HT(2C,) 5-HT3 and 5-HT4 receptors, but not the 5-HT(1D) receptor, mediate antinociception produced by 5-HT in the formalin test. The relevance of the 5-HT(1A) receptor is less clear because of the different effects of antagonist and agonist.
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Comparative Study
Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype.
Which of the three alpha2-adrenoceptor subtypes of alpha2A, alpha2B, or alpha2C mediates the neuroprotective effect of dexmedetomidine was examined in cell culture as well as in an in vivo model of neonatal asphyxia. Dexmedetomidine dose-dependently attenuated neuronal injury (IC50=83+/-1 nM) in neuronal-glial co-cultures derived from wild-type mice; contrastingly, dexmedetomidine did not exert neuroprotection in injured cells from transgenic mice (D79N) expressing dysfunctional alpha2A-adrenoceptors. An alpha2A-adrenoceptor subtype-preferring antagonist 2-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408) completely reversed dexmedetomidine-induced neuroprotection, while other subtype-preferring antagonists 2-[2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239) (alpha2B) and rauwolscine (alpha2C) had no significant effect on the neuroprotective effect of dexmedetomidine in neuronal-glial co-cultures. ⋯ Dexmedetomidine exhibited dose-dependent protection against brain matter loss in vivo (IC50=40.3+/-6.1 microg/kg) and improved the neurologic functional deficit induced by the hypoxic-ischemic insult. Protection by dexmedetomidine against hypoxic-ischemic-induced brain matter loss was reversed by the alpha2A-adrenoceptor subtype-preferring antagonist BRL44408; neither ARC239 nor rauwolscine reversed the neuroprotective effect of dexmedetomidine in vivo. Our data suggest that the neuroprotective effect of dexmedetomidine is mediated by activation of the alpha2A adrenergic receptor subtype.
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Migraine is a common neurological disorder that is associated with an increase in plasma calcitonin gene-related peptide (CGRP) levels. CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates intracranial blood vessels and transmits vascular nociception. Therefore, it is propounded that: (i) CGRP may have an important role in migraine pathophysiology, and (ii) inhibition of trigeminal CGRP release or CGRP-induced cranial vasodilatation may abort migraine. ⋯ Preclinical investigations in established migraine models that are predictive of antimigraine activity have shown that BIBN4096BS is a potent CGRP receptor antagonist and that it has antimigraine potential. Indeed, a recently published clinical study has reported that BIBN409BS is effective in treating acute migraine attacks without significant side effects. The present review will discuss mainly the potential role of CGRP in the pathophysiology of migraine and the various treatment modalities that are currently available to target this neuropeptide.