Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor-Gs Coupling

Tally M. Largent-Milnes, Wenhong Guo, Hoau Yan Wang, Lindsay H. Burns, Todd W Vanderah

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)-G protein coupling from Gi/o to Gs that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L5/L6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to Gs in the damaged (ipsilateral) spinal dorsal horn. This MOR-Gs coupling occurred without changing Gi/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-Gs coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-Gs coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this Gs coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-Gs coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. Perspective: The current study investigates whether Oxytrex (oxycodone with an ultra-low dose of naltrexone) alleviates mechanical and thermal hypersensitivities in an animal model of neuropathic pain over a period of 7 days, given locally or systemically. In this report, we first describe an injury-induced shift in μ-opioid receptor coupling from Gi/o to Gs, suggesting why a μ-opioid agonist may have reduced efficacy in the nerve-injured state. These data present a novel approach to neuropathic pain therapy.

Original languageEnglish (US)
Pages (from-to)700-713
Number of pages14
JournalJournal of Pain
Volume9
Issue number8
DOIs
StatePublished - Aug 2008

Fingerprint

Oxycodone
Naltrexone
Opioid Receptors
Neuralgia
Spinal Nerves
Ligation
Hyperalgesia
Opioid Analgesics
Spinal Cord
GTP-Binding Proteins
Synaptic Transmission
Peripheral Nerve Injuries
Narcotic Antagonists
Wounds and Injuries
Therapeutics
Oral Administration
Hypersensitivity
Animal Models
Hot Temperature
Pain

Keywords

  • μ-opioid receptor
  • allodynia
  • G protein coupling
  • hyperalgesia
  • Neuropathic pain
  • opioids
  • tolerance

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Clinical Neurology
  • Neurology
  • Nursing(all)

Cite this

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor-Gs Coupling. / Largent-Milnes, Tally M.; Guo, Wenhong; Wang, Hoau Yan; Burns, Lindsay H.; Vanderah, Todd W.

In: Journal of Pain, Vol. 9, No. 8, 08.2008, p. 700-713.

Research output: Contribution to journalArticle

Largent-Milnes, Tally M. ; Guo, Wenhong ; Wang, Hoau Yan ; Burns, Lindsay H. ; Vanderah, Todd W. / Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor-Gs Coupling. In: Journal of Pain. 2008 ; Vol. 9, No. 8. pp. 700-713.
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