Effect of the norepinephrine transporter (NET) inhibition on μ-opioid receptor (MOR)-induced anti-nociception in a bone cancer pain model

J Pharmacol Sci. 2014;125(3):264-73. doi: 10.1254/jphs.14081fp. Epub 2014 Jun 25.

Abstract

Although norepinephrine transporter (NET) inhibition has an additional effect on μ-opioid receptor (MOR)-mediated anti-nociception in inflammatory and neuropathic pain, its effect on cancer pain is not well characterized. We investigated the additional effect of NET inhibition on MOR activation using a mouse femur bone cancer (FBC) pain model by comparing the anti-nociceptive effect of the dual-acting opioids tramadol and tapentadol and the clinically used MOR-targeted opioids oxycodone and morphine. The anti-nociceptive effects of subcutaneously administered opioids were assessed using the von-Frey filament test. Oxycodone (1 - 10 mg/kg) and morphine (5 - 50 mg/kg) dose-dependently exhibited potent anti-nociceptive effects, whereas tramadol (10 - 56 mg/kg) and tapentadol (10 - 30 mg/kg) exhibited partial effects. Rota-rod analyses of tapentadol at a higher dose (> 30 mg/kg) showed a significant decrease in motor coordination, which was partially recovered by pretreatment with MOR or α(1)-adrenoceptor antagonists. The partial anti-nociceptive effect of tapentadol (30 mg/kg) was completely suppressed by a MOR antagonist, but not by α(1)- or α(2)-adrenoceptor antagonists, suggesting that neither α(1)-adrenoceptor- nor α(2)-adrenoceptor-mediated pathways are involved in anti-nociception in the FBC model. We conclude that addition of NET inhibition does not contribute to MOR-mediated anti-nociception in bone cancer pain.

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use*
  • Animals
  • Bone Neoplasms / complications*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Male
  • Mice, Inbred C3H
  • Morphine / administration & dosage
  • Morphine / pharmacology
  • Neoplasm Transplantation
  • Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Oxycodone / administration & dosage
  • Oxycodone / pharmacology
  • Oxycodone / therapeutic use
  • Pain / drug therapy*
  • Pain / etiology*
  • Phenols / administration & dosage
  • Phenols / pharmacology
  • Phenols / therapeutic use
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-1 / physiology
  • Receptors, Adrenergic, alpha-2 / physiology
  • Receptors, Opioid, mu / metabolism*
  • Receptors, Opioid, mu / physiology
  • Tapentadol
  • Tramadol / administration & dosage
  • Tramadol / pharmacology
  • Tramadol / therapeutic use
  • Tumor Cells, Cultured

Substances

  • Analgesics, Opioid
  • Norepinephrine Plasma Membrane Transport Proteins
  • Phenols
  • Receptors, Adrenergic, alpha-1
  • Receptors, Adrenergic, alpha-2
  • Receptors, Opioid, mu
  • Tramadol
  • Morphine
  • Oxycodone
  • Tapentadol