Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway.
Using a combined pharmacological and gene-deletion approach, we have delineated a novel mechanism of neurokinin-1 (NK-1) receptor-dependent hyperalgesia induced by proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons. Injections into the paw of sub-inflammatory doses of PAR2 agonists in rats and mice induced a prolonged thermal and mechanical hyperalgesia and elevated spinal Fos protein expression. This hyperalgesia was markedly diminished or absent in mice lacking the NK-1 receptor, preprotachykinin-A or PAR2 genes, or in rats treated with a centrally acting cyclooxygenase inhibitor or treated by spinal cord injection of NK-1 antagonists. Here we identify a previously unrecognized nociceptive pathway with important therapeutic implications, and our results point to a direct role for proteinases and their receptors in pain transmission.
Vergnolle
N
N
Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada.
Bunnett
N W
NW
Sharkey
K A
KA
Brussee
V
V
Compton
S J
SJ
Grady
E F
EF
Cirino
G
G
Gerard
N
N
Basbaum
A I
AI
Andrade-Gordon
P
P
Hollenberg
M D
MD
Wallace
J L
JL
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D006930:Hyperalgesia / Q000378:metabolism*; D007249:Inflammation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010146:Pain / Q000378:metabolism*; D011453:Prostaglandins / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000502:physiology; D018179:Receptors, Thrombin / Q000819:agonists / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000502:physiology
D011453:Prostaglandins; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1; D018179:Receptors, Thrombin; D013373:Substance P