Dynorphin A activates bradykinin receptors to maintain neuropathic pain.
Dynorphin A is an endogenous opioid peptide that produces non-opioid receptor-mediated neural excitation. Here we demonstrate that dynorphin induces calcium influx via voltage-sensitive calcium channels in sensory neurons by activating bradykinin receptors. This action of dynorphin at bradykinin receptors is distinct from the primary signaling pathway activated by bradykinin and underlies the hyperalgesia produced by pharmacological administration of dynorphin by the spinal route in rats and mice. Blockade of spinal B1 or B2 receptor also reverses persistent neuropathic pain but only when there is sustained elevation of endogenous spinal dynorphin, which is required for maintenance of neuropathic pain. These data reveal a mechanism for endogenous dynorphin to promote pain through its agonist action at bradykinin receptors and suggest new avenues for therapeutic intervention.
Lai
Josephine
J
Department of Pharmacology, University of Arizona Health Sciences Center, 1501 N. Campbell Ave., Tucson, Arizona 85724, USA. lai@u.arizona.edu
Luo
Miaw-Chyi
MC
Chen
Qingmin
Q
Ma
Shouwu
S
Gardell
Luis R
LR
Ossipov
Michael H
MH
Porreca
Frank
F
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D004399:Dynorphins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration; D009437:Neuralgia / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016037:Single-Blind Method; D013127:Spinal Nerves / Q000293:injuries / Q000378:metabolism*
D015220:Calcium Channels; D018002:Receptors, Bradykinin; D004399:Dynorphins; D002118:Calcium