European journal of pharmacology
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Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) in parkinsonian patients is known to lead to dyskinesia within a few years, and repeated administration of L-DOPA is also likely to alter the expression of kappa opioid receptors in the basal ganglia, especially the striatum and substantia nigra pars reticulata, suggesting that kappa opioid receptors might be deeply involved in motor functions. Therefore, effects of TRK-820 ((E)-N-[17-(cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan-6beta-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride), a selective kappa opioid receptor agonist, were investigated on rotational behavior in unilateral 6-hydroxydopamine (6-OHDA)-treated rats (hemi-parkinsonian rats) and on L-DOPA-induced dyskinesia produced by administering L-DOPA to hemi-parkinsonian rats for 3 weeks (dyskinesia rats). ⋯ Moreover, the development of L-DOPA-induced dyskinesia was suppressed by the 3-week co-administration of TRK-820 (3 and 10 microg/kg, s.c.) with L-DOPA. These results have suggested that TRK-820 ameliorates L-DOPA-induced dyskinesia with a moderate anti-parkinsonian effect by inhibiting L-DOPA-induced excessive dopamine release through kappa opioid receptors only in dyskinesia rats; therefore, TRK-820 is expected to become a useful agent for the treatment of L-DOPA-induced dyskinesia.
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This study assesses the effects of peripheral or intrathecal pre-treatment or post-treatment with micro, delta, kappa and nociceptin/orphanin FQ (NOP) opioid receptor agonists (morphine, U-50488 [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide hydrochloride], DADLE [D-Ala2-Leu5-enkephalin] and nociceptin, respectively) on formalin-induced secondary mechanical allodynia and hyperalgesia in rats. 1% Formalin injection produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term tactile secondary allodynia and hyperalgesia. Neither peripheral (into the formalin-injected paw) nor intrathecal morphine post-treatment reversed formalin-induced secondary allodynia and hyperalgesia. In contrast, morphine pre-treatment prevented the development of these pain behaviors. ⋯ In contrast, micro opioid receptors are more important at the beginning of the injury when the sensory system has not changed. NOP receptors participate diminishing both the development and maintenance of nociceptive behaviors. Results suggest that a barrage of afferent input induced by formalin injection initiates a long-term differential change in peripheral and spinal processing that affect the efficacy of opioid receptor agonists.
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Extracellular ATP is a signaling molecule that often serves as a danger signal to alert the immune system of tissue damage. This molecule activates P2 nucleotide receptors, that include the ionotropic P2X receptors and metabotropic P2Y receptors. Recently, it has been reported that ATP accumulates in the airways of both asthmatic patients and sensitized mice after allergen challenge. ⋯ Moreover, activation of neutrophils with cigarette smoke extract induced ATP release. Treatment of neutrophils with apyrase (catalyses the hydrolysis of ATP to yield AMP) and suramin (P2-receptor antagonist) abrogated the release of CXCL8 and elastase induced by cigarette smoke extract and exogenous ATP. These observations indicate that activation of purinergic signaling by cigarette smoke may take part in the pathogenesis of lung emphysema.