title: The influence of μ-opioid and noradrenaline reuptake inhibition in the modulation of pain responsive neurones in the central amygdala by tapentadol in rats with neuropathy.
abstract: Treatments for neuropathic pain are either not fully effective or have problematic side effects. Combinations of drugs are often used. Tapentadol is a newer molecule that produces analgesia in various pain models through two inhibitory mechanisms, namely central μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition. These two components interact synergistically, resulting in levels of analgesia similar to opioid analgesics such as oxycodone and morphine, but with more tolerable side effects. The right central nucleus of the amygdala (CeA) is critical for the lateral spinal ascending pain pathway, regulates descending pain pathways and is key in the emotional-affective components of pain. Few studies have investigated the pharmacology of limbic brain areas in pain models. Here we determined the actions of systemic tapentadol on right CeA neurones of animals with neuropathy and which component of tapentadol contributes to its effect. Neuronal responses to multimodal peripheral stimulation of animals with spinal nerve ligation or sham surgery were recorded before and after two doses of tapentadol. After the higher dose of tapentadol either naloxone or yohimbine were administered. Systemic tapentadol resulted in dose-dependent decrease in right CeA neuronal activity only in neuropathy. Both naloxone and yohimbine reversed this effect to an extent that was modality selective. The interactions of the components of tapentadol are not limited to the synergy between the MOR and α2-adrenoceptors seen at spinal levels, but are seen at this supraspinal site where suppression of responses may relate to the ability of the drug to alter affective components of pain.
authors.affiliation: Neuroscience Physiology & Pharmacology, Medical Sciences Building, University College London, Gower St, London WC1E 6BT, UK. Electronic address: m.goncalves@ucl.ac.uk.
authors.forename: Leonor
authors.initials: L
authors.lastname: Gonçalves
authors.affiliation: Neuroscience Physiology & Pharmacology, Medical Sciences Building, University College London, Gower St, London WC1E 6BT, UK. Electronic address: lauren.friend.11@ucl.ac.uk.
authors.forename: Lauren V
authors.initials: LV
authors.lastname: Friend
authors.affiliation: Neuroscience Physiology & Pharmacology, Medical Sciences Building, University College London, Gower St, London WC1E 6BT, UK. Electronic address: anthony.dickenson@ucl.ac.uk.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D066274:Central Amygdaloid Nucleus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D013127:Spinal Nerves / Q000293:injuries; D000077432:Tapentadol; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D009292:Narcotic Antagonists; D010636:Phenols; D017450:Receptors, Opioid, mu; D015016:Yohimbine; D009270:Naloxone; D000077432:Tapentadol; D009638:Norepinephrine
keywords: Neuropathy; Noradrenaline; Opioid; Rat; Right central amygdala; Tapentadol