A Novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism

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  • Gris, Pavel
    • Other Affiliation: Center for Neurosensory Disorders
  • Gauthier, Josee
    • Other Affiliation: Center for Neurosensory Disorders
  • Cheng, Philip
    • Other Affiliation: Center for Neurosensory Disorders
  • Gibson, Dustin G.
    • Other Affiliation: Center for Neurosensory Disorders
  • Gris, Denis
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Laur, Oskar
    • Other Affiliation: Yerkes Research Center - Division of Microbiology, Emory University, Atlanta, GA, 30329, USA
  • Pierson, John
    • Other Affiliation: Center for Neurosensory Disorders
  • Wentworth, Sean
    • Other Affiliation: Center for Neurosensory Disorders
  • Nackley, Andrea
    • Other Affiliation: Center for Neurosensory Disorders
  • Maixner, William
    • Other Affiliation: Center for Neurosensory Disorders
  • Diatchenko, Luda
    • Other Affiliation: Center for Neurosensory Disorders
Abstract
  • Abstract: Background: Opioids are the most widely used analgesics for the treatment of clinical pain. They produce their therapeutic effects by binding to μ-opioid receptors (MORs), which are 7 transmembrane domain (7TM) G-proteincoupled receptors (GPCRs), and inhibiting cellular activity. However, the analgesic efficacy of opioids is compromised by side-effects such as analgesic tolerance, dependence and opioid-induced hyperalgesia (OIH). In contrast to opioid analgesia these side effects are associated with cellular excitation. Several hypotheses have been advanced to explain these phenomena, yet the molecular mechanisms underlying tolerance and OIH remain poorly understood. Results: We recently discovered a new human alternatively spliced isoform of MOR (MOR1K) that is missing the Nterminal extracellular and first transmembrane domains, resulting in a 6TM GPCR variant. To characterize the pattern of cellular transduction pathways activated by this human MOR1K isoform, we conducted a series of pharmacological and molecular experiments. Results show that stimulation of MOR1K with morphine leads to excitatory cellular effects. In contrast to stimulation of MOR1, stimulation of MOR1K leads to increased Ca2+ levels as well as increased nitric oxide (NO) release. Immunoprecipitation experiments further reveal that unlike MOR1, which couples to the inhibitory Gαi/o complex, MOR1K couples to the stimulatory Gαs complex. Conclusion: The major MOR1 and the alternative MOR1K isoforms mediate opposite cellular effects in response to morphine, with MOR1K driving excitatory processes. These findings warrant further investigations that examine animal and human MORK1 expression and function following chronic exposure to opioids, which may identify MOR1K as a novel target for the development of new clinically effective classes of opioids that have high analgesic efficacy with diminished ability to produce tolerance, OIH, and other unwanted side-effects.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • Pavel Gris et al.; licensee BioMed Central Ltd.
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Journal title
  • Molecular Pain
Journal volume
  • 6
Journal issue
  • 1
Page start
  • 33
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1744-8069
Bibliographic citation
  • Molecular Pain. 2010 Jun 02;6(1):33
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • August 23, 2012

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