Journal of pharmacological sciences
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Previous in vitro studies have shown that the degradation of [Met(5)]enkephalin-Arg(6)-Phe(7) during incubation with cerebral membrane preparations is largely prevented by a mixture of three peptidase inhibitors: amastatin, captopril, and phosphoramidon. The present in vivo study shows that the inhibitory effect of [Met(5)]enkephalin-Arg(6)-Phe(7) administered intra-third-ventricularly on the tail-flick response was increased more than 1000-fold by the intra-third-ventricular pretreatment with three peptidase inhibitors. The antinociceptive effect produced by the [Met(5)]enkephalin-Arg(6)-Phe(7) in rats pretreated with any combination of two peptidase inhibitors was significantly smaller than that in rats pretreated with three peptidase inhibitors, indicating that any residual single peptidase could inactivate significant amounts of the [Met(5)]enkephalin-Arg(6)-Phe(7). The present data, together with those obtained from previous studies, clearly show that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play important roles in the inactivation of endogenous opioid peptides, such as [Met(5)]enkephalin, [Met(5)]enkephalin-Arg(6)-Phe(7), [Met(5)]enkephalin-Arg(6)-Gly(7)-Leu(8), and dynorphin A (1-8), administered intra-third-ventricularly to rats.
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We have previously demonstrated that the antiepileptic drug zonisamide supraspinally generates analgesic effects on thermal and mechanical hypersensitivity in mice after peripheral nerve injury. To further establish the neurochemical basis for the supraspinally mediated analgesic action of zonisamide, we measured spinal noradrenaline (NA), 3-methoxy-4-hydroxyphenyleneglycol (MHPG), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and dopamine (DA) contents using HPLC with electrochemical detection in a murine neuropathic pain model that was prepared by partial ligation of the sciatic nerve (Seltzer model). ⋯ Moreover, the effectiveness of i.p. or i.c.v. administered zonisamide at reducing thermal and mechanical hypersensitivity was not influenced by intrathecally administered yohimbine (3 mug), an alpha(2)-adrenergic receptor antagonist. Thus, it appears that the supraspinally mediated analgesic effects of zonisamide are independent of the descending monoaminergic pain inhibitory system.
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To clarify the role of NO in mouse anaphylactic hypotension, effects of a nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), on antigen-induced hypotension and portal hypertension were determined in anesthetized BALB/c mice. Systemic arterial pressure (Psa), central venous pressure (Pcv), and portal venous pressure (Ppv) were directly and simultaneously measured. Mice were first sensitized with ovalbumin, and then the injection of antigen was used to decrease Psa and increase Ppv. ⋯ Furthermore, methylene blue did not improve systemic hypotension induced by Compound 48/80 (4.5 mg/kg), a mast cell degranulator, which can produce non-immunological anaphylactoid reactions. These data show in anesthetized BALB/c mice that L-NAME attenuated anaphylactic hypotension without affecting portal hypertension. This beneficial effect of L-NAME appears not to depend on the soluble guanylate cyclase pathway.
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In the present study, we investigated whether the peripherally acting micro-opioid receptor agonist loperamide would inhibit allodynia in the non-inflamed dermatome of mice with herpetic pain. Subcutaneous (s.c.) injection of loperamide (1 and 3 mg/kg) inhibited allodynia. Local (intraplantar) injection of loperamide (1 and 5 microg/site) also produced an anti-allodynic effect. ⋯ In addition, there were no cross-tolerance between local opioids (morphine and loperamide) and systemic morphine. These results suggest that stimulation of peripheral micro-opioid receptors suppresses herpetic allodynia without tolerance development. The non-narcotic micro-opioid receptor agonist loperamide may relieve acute herpetic pain in patients with herpes zoster.
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Itching is the most important symptom in atopic dermatitis because the persistent scratching in response to itching aggravates the disease. However, the etiologic mechanisms of itching in atopic dermatitis remain uncertain. HR-1 hairless mice fed a special diet, HR-AD, develop atopic dermatitis-like symptoms with prolonged scratching episodes. ⋯ Furthermore, after cessation of HR-AD feeding, the reduction in intraepidermal nerve fibers coincided with decreased scratching. Neither the prolongation of scratching nor the increase in intraepidermal nerve fibers was affected by dexamethasone treatment. Thus, the increased number of intraepidermal nerve fibers could be involved in the aggravation of itch-related scratching observed in this model.