title: Neuropathic plasticity in the opioid and non-opioid actions of dynorphin A fragments and their interactions with bradykinin B2 receptors on neuronal activity in the rat spinal cord.
abstract: Dynorphin A is an endogenous opioid peptide derived from the precursor prodynorphin. The proteolytic fragment dynorphin A (1-17) exhibits inhibitory effects via opioid receptors. Paradoxically, the activity of the dynorphin system increases with chronic pain and neuropathy is associated with the up-regulation of dynorphin biosynthesis. Dynorphin A (1-17) is cleaved in vivo to produce a non-opioid fragment, dynorphin A (2-17). Previously, a mechanism by which the non-opioid fragment promotes pain through agonist action at bradykinin receptors was revealed. Bradykinin receptor expression is up-regulated after nerve injury and both a truncated version of non-opioid fragment dynorphin A (2-17), referred to as 'Ligand 10', and novel bradykinin receptor antagonist 'Ligand 14', are known to bind to the bradykinin receptor. Here we show that Ligand 10 facilitates the response of wide dynamic range (WDR) neurons to innocuous and noxious mechanical stimuli in neuropathic, but not naïve, animals, while Ligand 14 exhibits inhibitory effects in neuropathic animals only. Furthermore, we reveal an inhibitory effect of Ligand 14 in naïve animals by pre-dosing with either Ligand 10 or a 5-HT3 receptor agonist to reflect activation of descending excitatory drives. Thus remarkably, by mimicking pro-excitatory pharmacological changes that occur after nerve injury in a naïve animal, we induce a state whereby the inhibitory actions of Ligand 14 are now effective. Ultimately our data support an increasing number of studies that suggest that blocking spinal bradykinin receptors may have a therapeutic potential in chronic pain states, here, in particular, in neuropathic pain.
authors.affiliation: Department of Neuroscience, Pharmacology and Physiology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: Kirsty.bannister@ucl.ac.uk.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Bannister
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Yeon Sun
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, Pharmacology and Physiology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Leonor
authors.initials: L
authors.lastname: Goncalves
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Neuroscience, Pharmacology and Physiology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D065094:Bradykinin B2 Receptor Antagonists / Q000494:pharmacology*; D004195:Disease Models, Animal; D004399:Dynorphins / Q000494:pharmacology*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D010812:Physical Stimulation; D017207:Rats, Sprague-Dawley; D058827:Serotonin 5-HT3 Receptor Agonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000503:physiopathology; D013127:Spinal Nerves / Q000293:injuries
chemical_list: D018712:Analgesics, Non-Narcotic; D065094:Bradykinin B2 Receptor Antagonists; D010446:Peptide Fragments; D058827:Serotonin 5-HT3 Receptor Agonists; D004399:Dynorphins; C082245:dynorphin (2-17)
keywords: Bradykinin receptor; Dynorphin A; Neuropathy; Non-opioid; Opioid; Spinal cord