title: Mu-opioid and noradrenergic α(2)-adrenoceptor contributions to the effects of tapentadol on spinal electrophysiological measures of nociception in nerve-injured rats.
abstract: Multiple pathological mechanisms at multiple sensory sites may underlie the pain that follows nerve injury. This provides a basis for recommending more than one agent, either sequentially or in combination, for its treatment. According to this premise, new drugs that combine different mechanisms of analgesic action in a single molecule are gaining momentum, such as tapentadol which stimulates mu-opioid receptors (MOR) and acts as a noradrenaline reuptake inhibitor (NRI) in the CNS. Tapentadol is currently indicated for treating moderate to severe acute and severe chronic pain, and here we demonstrate its efficacy in an animal model of ongoing neuropathic pain. In particular, we performed a series of in vivo electrophysiological tests in spinal nerve ligated and sham-operated rats to show that systemic tapentadol (1 and 5mg/kg) dose-dependently reduced evoked responses of spinal dorsal horn neurones to a range of peripheral stimuli, including brush, punctate mechanical and thermal stimuli. Furthermore, we showed that spinal application of the selective α(2)-adrenoceptor antagonist atipamezole, or alternatively the mu-opioid receptor antagonist naloxone, produced near complete reversal of tapentadol's inhibitory effects, which suggests not only that the spinal cord is the key site of tapentadol's actions, but also that no pharmacology other than MOR-NRI is involved in its analgesia. Moreover, according to the extent that the antagonists reversed tapentadol's inhibitions in sham and SNL rats, we suggest that there may be a shift from predominant opioid inhibitory mechanisms in control animals, to predominant noradrenergic inhibition in neuropathic animals.
authors.affiliation: Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Bee
authors.forename: Kirsty
authors.initials: K
authors.lastname: Bannister
authors.forename: Wahida
authors.initials: W
authors.lastname: Rahman
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D005071:Evoked Potentials / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013127:Spinal Nerves / Q000473:pathology; D000077432:Tapentadol
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000701:Analgesics, Opioid; D007093:Imidazoles; D009292:Narcotic Antagonists; D010636:Phenols; D018341:Receptors, Adrenergic, alpha-2; D017450:Receptors, Opioid, mu; C050701:atipamezole; D009270:Naloxone; D000077432:Tapentadol