The Journal of pharmacology and experimental therapeutics
-
J. Pharmacol. Exp. Ther. · Dec 2004
Opioid receptor involvement in food deprivation-induced feeding: evaluation of selective antagonist and antisense oligodeoxynucleotide probe effects in mice and rats.
Central administration of general and selective opioid receptor subtype antagonists in the rat has revealed a substantial role for mu, a moderate role for kappa, and a minimal role for delta receptors in the mediation of deprivation-induced feeding. Antisense probes directed against the kappa opioid receptor (KOP), nociceptin opioid receptor (NOP), and delta opioid receptor (DOP) genes in rats result in reductions similar to kappa and delta antagonists, whereas antisense probes directed against the mu opioid receptor (MOP) gene produced modest reductions relative to mu antagonists, suggesting that isoforms of the MOP gene may mediate deprivation-induced feeding. Since these isoforms were initially identified in mice, the present study compared the effects of general and selective opioid receptor antagonists on deprivation-induced feeding in rats and mice and antisense probes directed against exons of the MOP, DOP, KOP, and NOP genes on deprivation-induced feeding in the mouse. ⋯ In contrast, mice, but not rats, displayed reductions in deprivation-induced intake following delta antagonism as well as DOP antisense probes, suggesting a species-specific role for the delta receptor. Antisense probes directed against the KOP and NOP genes also reduced deprivation-induced intake in mice in a manner similar to kappa antagonism. However, the significant reductions in deprivation-induced feeding following antisense probes directed against either exons 2, 4, 7, 8, or 13 of the MOP gene were modest compared with mu antagonism, suggesting a role for multiple mu-mediated mechanisms.
-
J. Pharmacol. Exp. Ther. · Dec 2004
Differential sensitivity of N- and P/Q-type Ca2+ channel currents to a mu opioid in isolectin B4-positive and -negative dorsal root ganglion neurons.
Opioids have a selective effect on nociception with little effect on other sensory modalities. However, the cellular mechanisms for this preferential effect are not fully known. Two broad classes of nociceptors can be distinguished based on their growth factor requirements and binding to isolectin B4(IB4). ⋯ Furthermore, double labeling revealed that there was a significantly higher mu opioid receptor immunoreactivity in IB4-negative than IB4-positive cells. Thus, these data suggest that N-and P/Q-type Ca2+ currents are more sensitive to inhibition by the mu opioids in IB4-negative than IB4-positive DRG neurons. The differential sensitivity of voltage-gated Ca2+ channels to the mu opioids in subsets of DRG neurons may constitute an important analgesic mechanism of mu opioids.
-
J. Pharmacol. Exp. Ther. · Dec 2004
Hepatobiliary disposition of the metabolically stable opioid peptide [D-Pen2, D-Pen5]-enkephalin (DPDPE): pharmacokinetic consequences of the interplay between multiple transport systems.
[D-Pen2,D-Pen5]-Enkephalin (DPDPE) is excreted extensively into the bile. Although DPDPE is transported by P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (Mrp2) has been identified as an important mechanism for DPDPE transport across the canalicular membrane of the hepatocyte. The present studies determined the relative impact of Mrp2 and P-gp on the hepatobiliary disposition of [3H]DPDPE in isolated perfused rat livers (IPLs). ⋯ Results of pharmacokinetic modeling were consistent with the hypothesis that GF120918 inhibited a [3H]DPDPE basolateral excretion mechanism. Mrp2 is the primary mechanism for [3H]DPDPE biliary excretion, and P-gp facilitates excretion of [3H]DPDPE only in the absence of functional Mrp2. [3H]DPDPE is a substrate for a basolateral efflux mechanism that is sensitive to inhibition by GF120918. These data emphasize the importance of using appropriate model systems and comprehensive pharmacokinetic modeling in elucidating the complex interplay between multiple transport systems.