Opioid drugs used in the treatment of severe pain are known to produce tolerance that requires a dose increase to maintain a sufficient analgesic effect. As this is connected with side effects such as respiratory depression, it is highly desirable to avoid or at least attenuate the development of tolerance. Closely related, but in some respect dissociable, is the phenomenon of physical dependen...

mu opioid receptors are targets of native opioid peptides and addictive analgesic drugs. A major clinical liability of opiate drugs is their ability to cause physiological tolerance. Individual opiates, such as morphine and etorphine, differ both in their ability to promote physiological tolerance and in their effects on receptor regulation by endocytosis. Here, we demonstrate that arrestins pl...

In the nervous system, the interaction of opioids like morphine and its derivatives, with the G protein-coupled Mu-opioid receptor (MOR) provokes the development of analgesic tolerance, as well as physical dependence. Tolerance implies that increasing doses of the drug are required to achieve the same effect, a phenomenon that contributes significantly to the social problems surrounding recreat...

The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are les...

We investigated whether chronic, in vivo administration of U50,488H, a kappa-1 opioid agonist, caused the development of tolerance to both the electrophysiological effects of applied kappa opioids and endogenously released dynorphins. In hippocampal slices from drug-naive guinea pigs, application of U69,593, a kappa-1 agonist, produced a concentration-dependent inhibition (EC50 = 20 nM) of the ...

Opioids are some of the most efficacious analgesics used in humans. Prolonged administration of opioids, however, often causes the development of drug tolerance, thus limiting their effectiveness. To explore the molecular basis of those mechanisms that may contribute to opioid tolerance, we have isolated a cDNA for the human mu opioid receptor, the target of such opioid narcotics as morphine, c...

Our previous studies indicate that oxycodone is a putative kappa-opioid agonist, whereas morphine is a well documented micro-opioid agonist. Because there is limited information regarding the development of tolerance to oxycodone, this study was designed to 1) document the development of tolerance to the antinociceptive effects of chronically infused i.v. oxycodone relative to that for i. v. mo...

Studies suggest that acute and chronic opioids can regulate the cAMP-dependent protein kinase (PKA) signaling pathway and that changes in this pathway may be involved in opioid tolerance. In the present study, we examined the role of cAMP-PKA on mu-opioid receptor downregulation and tolerance in mice. Mice were injected intracerebroventricular (i.c.v.) and intrathecal (i.t.) once a day with an ...