Opioid drugs acting at the mu opioid receptor (muOR), such as morphine, represent the most commonly prescribed analgesics for the clinical management of moderate to severe pain. However, the clinical use of muOR agonists is limited by the occurrence of undesirable effects such as respiratory depression and the tendency to produce tolerance and/or dependence with repeated administration. delta opioid receptor (deltaOR) activation produces antinociception with reportedly less deleterious effects when compared to muOR activation. However, animal studies have revealed that deltaOR-mediated antinociceptive effects are modest compared to muOR-elicited ones. Thus, we studied the regulation of deltaOR trafficking in the rodent central nervous system with the intention of modifying the density of this receptor at the cell surface and thereby improve deltaOR agonist potency. Stimulation with morphine for 48 hours produced increased deltaOR cell surface density both in vitro in primary cortical neurons in culture and in vivo in neurons within the dorsal horn of the spinal cord of rodents. This enhanced deltaOR cell surface density was a trafficking event and was not due to an overall increase in deltaOR expression. In vivo, the increased deltaOR cell surface density was accompanied with enhanced antinociceptive potency of intrathecally administered muOR agonists and augmented internalization of a fluorescent deltaOR agonist in the dorsal horn. This effect was observed following pretreatment with various muOR agonists and was abolished in muOR knock-out mice, demonstrating that activation of muOR was critical for enhanced targeting of deltaOR to neuronal plasma membranes and the observed increased antinociceptive responses. These changes in deltaOR function and subcellular localization were not associated with the development of tolerance to muOR agonists and were reversed 48 hours after the cessation of treatment with morphine. This muOR-induced enha
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84298 |
| Date | January 2003 |
| Creators | Morinville, Anne |
| Contributors | Beaudet, Alain (advisor), Collier, Brian (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology and Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002032104, proquestno: AAINQ98331, Theses scanned by UMI/ProQuest. |
Page generated in 0.0022 seconds