Neuropeptides
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Comparative Study
Blockade of calcitonin gene-related peptide release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288.
The pathophysiological basis for the pain of migraine has been the subject of substantial attention and must include activation of elements of the trigeminal innervation of the cranial vessels, the trigeminovascular system. Recently, consideration of trigeminal-evoked neurogenic plasma protein extravasation (PPE) as a model for the pain has driven the search for compounds with specific anti-extravasation properties. Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. ⋯ At a PPE-inhibitory dose in rat (100 ng/kg intravenously) CP122, 288 had no effect on CGRP release (77+/-6 pmol/L) whereas at a clinically relevant dose (50 microgram/kg intravenously) avitriptan blocked CGRP release. This study demonstrates that the potent inhibitor of PPE, CP122, 288, which has been shown in clinical trials to be ineffective in treating acute migraine attacks, had no effect on CGRP release, whereas the effective anti-migraine drug and relatively impotent inhibitor of PPE, avitriptan, blocked CGRP release. These data emphasize the importance of CGRP release and its possible independence from PPE in migraine and more importantly suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.
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This study investigates the effect and some of the mechanisms involved following systemic treatment of mice with Mycobacterium bovis bacillus Calmette-Guérin (BCG) (1 dose per animal containing 6.4 x 10(4) colony-forming units (CFu) 20-60 days beforehand) on modulation of the kinin B1 receptor agonist-induced nociception and oedema formation in the formalin test. Intraplantar (i.p.l.) co-injection of des-Arg9-bradykinin (4-32 nmol/paw) or des-Arg10-kallidin (1-15 nmol/paw), together with sub-maximal concentrations of formalin (0.01 or 0.5%), potentiated (P < 0.01) both pain phases and the paw oedema caused by formalin in animals pre-treated with saline. However, when animals were pre-treated with BCG, the dose-response curves for both B1 agonists were shifted 2 to 8-fold to the left. ⋯ Dexamethasone (0.5 mg/kg, s.c.), given every 24 h, from day 0 to 30-45, inhibited significantly the potentiation of nociceptive response and oedema formation caused by i.p.l. co-injection of formalin plus des-Arg9-bradykinin, while indomethacin (2 mg/kg, i.p.) or phenidone (30 mg/kg, i.p.), given 1 h prior, caused less inhibition. These data show that the long-term systemic treatment of mice with BCG produced dose-related potentiation of B1 receptor agonist-mediated nociception and oedema formation, without affecting similar responses caused by the B2 receptor agonist tyrosine8-bradykinin. Thus, systemic treatment of mice with BCG induces upregulation of B1 receptors, without affecting B2-mediated responses, by a mechanism that seems to be secondary to cytokine release.
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The intradermal (i.d.) injection of NK1 receptor antagonists GR 82334 and FK 888 (1-50 pmol/paw), in association with formalin, produced graded inhibition of the early but not the late phase of the formalin test. The NK2, SR 48968 and NK3 SR 142801 receptor antagonists (1-50 pmol/paw) were effective in inhibiting both phases of the formalin model. Co-injection of NK1, (FK 888, GR 82334), NK2 (SR 48968) or NK3 (SR 142801) receptor antagonists with capsaicin dose-dependently attenuated capsaicin-induced licking. ⋯ These results indicate that tachykinin receptor antagonists, acting through NK1, NK2 and NK3 receptors, produce powerful antinociception when injected i.d. or by i.c.v. route against both formalin- and capsaicin-induced licking, being more efficacious against the latter model of nociception. The action of NK3 receptor antagonist given i.d. was mediated through an opioid mechanism sensitive to naloxone. However, when injected i.c.v., the antinociception caused by NK1, NK2 or NK3 receptor antagonists was largely reversed by naloxone when assessed in the formalin test, suggesting a distinct mechanism of action.
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Comparative Study
Differential modulation of mu- and delta-opioid antinociception by neuropeptide FF receptors in young mice.
The ability of neuropeptide FF (NPFF) to modulate mu- and delta-opioid-induced analgesia by intracerebroventricular administration was compared in adults and 14-day-old mice. In adults, opioid-induced analgesia was predominantly mediated by mu-receptors whereas mu- and delta-receptors were equally involved in pups. An NPFF analog, 1 DMe, reduced the analgesic effect of DAGO and [D. ⋯ Ala2]deltorphin-I-induced analgesia. Dose-response curves for 1DMe in the presence of naltrindole or naltrexone, delta- and mu-opioid selective antagonists respectively, indicate that 1DMe preferentially reversed mu-receptor-mediated but increased delta-receptor-mediated analgesia. These findings demonstrate differences in control of mu- and delta-induced analgesia by NPFF receptors.
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The present study was designed to investigate the modulatory effects of blockade of spinal histamine receptors on antinociception induced by spinally administered morphine, beta-endorphin and U50, 488H. The effects of intrathecal (i.t.) injections with cyproheptadine (a histamine-1 (H1) receptor antagonist), ranitidine (an H2 receptor antagonist), or thioperamide (an H3 receptor antagonist) injected i.t., on the antinociception induced by morphine, beta-endorphin or trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzeocetamide (U50, 488H) injected intrathecally (i.t.) were studied. The antinociception was assayed using the tail-flick test. ⋯ Our results indicate that spinal H1 receptors may be involved in the production of antinociception induced by spinally applied morphine or beta-endorphin- but not U50, 488H. Spinal H2 receptors appear to be involved in spinally administered morphine-, beta-endorphin- and U50, 488H-induced antinociception. Supraspinal histamine H3 receptors may be involved in the production of antinociception induced by supraspinally applied beta-endorphin or U50, 488H, but not morphine.