title: Opioid and noradrenergic contributions of tapentadol in experimental neuropathic pain.
abstract: Tapentadol is a dual action molecule with mu opioid agonist and norepinephrine (NE) reuptake blocking activity that has recently been introduced for the treatment of moderate to severe pain. The effects of intraperitoneal (i.p.) morphine (10mg/kg), tapentadol (10 or 30 mg/kg) or duloxetine (30 mg/kg), a norepinephrine/serotonin (NE/5HT) reuptake inhibitor, were evaluated in male, Sprague-Dawley rats with spinal nerve ligation (SNL) or sham surgery. Additionally, the effects of these drugs on spinal cerebrospinal fluid (CSF) NE levels were quantified. Response thresholds to von Frey filament stimulation decreased significantly from baseline in SNL, but not sham, operated rats. Duloxetine, tapentadol and morphine produced significant and time-related reversal of tactile hypersensitivity. Duloxetine significantly increased spinal CSF NE levels in both sham and SNL rats and no significant differences were observed in these groups. Tapentadol (10 mg/kg) produced a significant increase in spinal NE levels in SNL, but not in sham, rats. At the higher dose (30 mg/kg), tapentadol produced a significant increase in spinal CSF NE levels in both SNL and sham groups; however, spinal NE levels were elevated for an extended period in the SNL rats. This could be detected 30 min following tapentadol (30 mg/kg) in both sham and SNL groups. Surprisingly, while the dose of morphine studied reversed tactile hypersensitivity in nerve-injured rats, CSF NE levels were significantly reduced in both sham- and SNL rats. The data suggest that tapentadol elicits enhanced elevation in spinal NE levels in a model of experimental neuropathic pain offering a mechanistic correlate to observed clinical efficacy in this pain state.
authors: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA. Electronic address: frankp@u.arizona.edu.
authors: Diana S
authors: DS
authors: Meske
authors: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors: Jennifer Y
authors: JY
authors: Xie
authors: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors: Janice
authors: J
authors: Oyarzo
authors: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors: Hamid
authors: H
authors: Badghisi
authors: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors: Michael H
authors: MH
authors: Ossipov
authors: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors: Frank
authors: F
authors: Porreca
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D000068736:Duloxetine Hydrochloride; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009437:Neuralgia / Q000188:drug therapy*; D009638:Norepinephrine / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects; D013127:Spinal Nerves / Q000187:drug effects*; D000077432:Tapentadol; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D010636:Phenols; D017450:Receptors, Opioid, mu; D013876:Thiophenes; D009020:Morphine; D000068736:Duloxetine Hydrochloride; D000077432:Tapentadol; D009638:Norepinephrine
keywords: Noradrenergic; Norepinephrine reuptake inhibition; Opioid; Spinal norepinephrine; Tapentadol
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