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

Kirsty Bannister, Yeon Sun Lee, Leonor Goncalves, Frank Porreca, Josephine Lai, Anthony H. Dickenson

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)375-383
Number of pages9
JournalNeuropharmacology
Volume85
DOIs
StatePublished - 2014

Fingerprint

Bradykinin B2 Receptors
Dynorphins
Opioid Analgesics
Spinal Cord
Bradykinin Receptors
Ligands
Chronic Pain
Serotonin 5-HT3 Receptor Agonists
Receptors, Serotonin, 5-HT3
Opioid Peptides
Wounds and Injuries
Opioid Receptors
Neuralgia
Up-Regulation
Pharmacology
Neurons
Pain

Keywords

  • Bradykinin receptor
  • Dynorphin A
  • Neuropathy
  • Non-opioid
  • Opioid
  • Spinal cord

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

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. / Bannister, Kirsty; Lee, Yeon Sun; Goncalves, Leonor; Porreca, Frank; Lai, Josephine; Dickenson, Anthony H.

In: Neuropharmacology, Vol. 85, 2014, p. 375-383.

Research output: Contribution to journalArticle

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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 na{\"i}ve, animals, while Ligand 14 exhibits inhibitory effects in neuropathic animals only. Furthermore, we reveal an inhibitory effect of Ligand 14 in na{\"i}ve 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 na{\"i}ve 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.",
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