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

Publication ,  Journal Article
Gris, P; Gauthier, J; Cheng, P; Gibson, DG; Gris, D; Laur, O; Pierson, J; Wentworth, S; Nackley, AG; Maixner, W; Diatchenko, L
Published in: Mol Pain
June 2, 2010

BACKGROUND: Opioids are the most widely used analgesics for the treatment of clinical pain. They produce their therapeutic effects by binding to mu-opioid receptors (MORs), which are 7 transmembrane domain (7TM) G-protein-coupled 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 N-terminal 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 Galphai/o complex, MOR1K couples to the stimulatory Galphas 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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Published In

Mol Pain

DOI

EISSN

1744-8069

Publication Date

June 2, 2010

Volume

6

Start / End Page

33

Location

United States

Related Subject Headings

  • Receptors, Opioid, mu
  • Protein Isoforms
  • Nitric Oxide
  • Neurology & Neurosurgery
  • Morphine
  • Humans
  • GTP-Binding Proteins
  • Cyclic AMP
  • Chlorocebus aethiops
  • Calcium
 

Citation

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Gris, P., Gauthier, J., Cheng, P., Gibson, D. G., Gris, D., Laur, O., … Diatchenko, L. (2010). A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism. Mol Pain, 6, 33. https://doi.org/10.1186/1744-8069-6-33
Gris, Pavel, Josee Gauthier, Philip Cheng, Dustin G. Gibson, Denis Gris, Oskar Laur, John Pierson, et al. “A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism.Mol Pain 6 (June 2, 2010): 33. https://doi.org/10.1186/1744-8069-6-33.
Gris P, Gauthier J, Cheng P, Gibson DG, Gris D, Laur O, et al. A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism. Mol Pain. 2010 Jun 2;6:33.
Gris, Pavel, et al. “A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism.Mol Pain, vol. 6, June 2010, p. 33. Pubmed, doi:10.1186/1744-8069-6-33.
Gris P, Gauthier J, Cheng P, Gibson DG, Gris D, Laur O, Pierson J, Wentworth S, Nackley AG, Maixner W, Diatchenko L. A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism. Mol Pain. 2010 Jun 2;6:33.
Journal cover image

Published In

Mol Pain

DOI

EISSN

1744-8069

Publication Date

June 2, 2010

Volume

6

Start / End Page

33

Location

United States

Related Subject Headings

  • Receptors, Opioid, mu
  • Protein Isoforms
  • Nitric Oxide
  • Neurology & Neurosurgery
  • Morphine
  • Humans
  • GTP-Binding Proteins
  • Cyclic AMP
  • Chlorocebus aethiops
  • Calcium