Clinically employed opioid analgesics produce antinociception via μ-δ Opioid receptor heteromers in rhesus monkeys

Ajay S. Yekkirala, Matthew L. Banks, Mary M. Lunzer, Stevens S. Negus, Kenner C. Rice, Philip S Portoghese

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Morphine and related drugs are widely employed as analgesics despite the side effects associated with their use. Although morphine is thought to mediate analgesia through mu opioid receptors, delta opioid receptors have been implicated in mediating some side effects such as tolerance and dependence. Here we present evidence in rhesus monkeys that morphine, fentanyl, and possibly methadone selectively activate mu-delta heteromers to produce antinociception that is potently antagonized by the delta opioid receptor antagonist, naltrindole (NTI). Studies with HEK293 cells expressing mu-delta heteromeric opioid receptors exhibit a similar antagonism profile of receptor activation in the presence of NTI. In mice, morphine was potently inhibited by naltrindole when administered intrathecally, but not intracerebroventricularly, suggesting the possible involvement of mu-delta heteromers in the spinal cord of rodents. Taken together, these results strongly suggest that, in primates, mu-delta heteromers are allosterically coupled and mediate the antinociceptive effects of three clinically employed opioid analgesics that have been traditionally viewed as mu-selective. Given the known involvement of delta receptors in morphine tolerance and dependence, our results implicate mu-delta heteromers in mediating both antinociception and these side effects in primates. These results open the door for further investigation in humans.

Original languageEnglish (US)
Pages (from-to)720-727
Number of pages8
JournalACS Chemical Neuroscience
Volume3
Issue number9
DOIs
StatePublished - Sep 19 2012

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naltrindole
delta Opioid Receptor
Opioid Receptors
Macaca mulatta
Morphine
Opioid Analgesics
Primates
Morphine Dependence
Narcotic Antagonists
mu Opioid Receptor
HEK293 Cells
Methadone
Fentanyl
Analgesia
Analgesics
Rodentia
Spinal Cord
Chemical activation
Cells
Pharmaceutical Preparations

Keywords

  • Allosterism
  • Analgesics
  • GPCR heteromers
  • opioid antagonism
  • primates

Cite this

Clinically employed opioid analgesics produce antinociception via μ-δ Opioid receptor heteromers in rhesus monkeys. / Yekkirala, Ajay S.; Banks, Matthew L.; Lunzer, Mary M.; Negus, Stevens S.; Rice, Kenner C.; Portoghese, Philip S.

In: ACS Chemical Neuroscience, Vol. 3, No. 9, 19.09.2012, p. 720-727.

Research output: Contribution to journalArticle

Yekkirala, Ajay S. ; Banks, Matthew L. ; Lunzer, Mary M. ; Negus, Stevens S. ; Rice, Kenner C. ; Portoghese, Philip S. / Clinically employed opioid analgesics produce antinociception via μ-δ Opioid receptor heteromers in rhesus monkeys. In: ACS Chemical Neuroscience. 2012 ; Vol. 3, No. 9. pp. 720-727.
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