Spinal dynorphin and bradykinin receptors maintain inflammatory hyperalgesia.
An upregulation of the endogenous opioid, dynorphin A, in the spinal cord is seen in multiple experimental models of chronic pain. Recent findings implicate a direct excitatory action of dynorphin A at bradykinin receptors to promote hyperalgesia in nerve injured rats, and its upregulation may promote, rather than counteract, enhanced nociceptive input due to injury. Here we examined a model of inflammatory pain by unilateral injection of complete Freund's adjuvant (CFA) into the rat hind paw. Rats exhibited tactile hypersensitivity and thermal hyperalgesia in the inflamed paw by 6 hours after CFA injection, whereas a significant elevation of prodynorphin transcripts in the lumbar spinal cord was seen at day 3 but not at 6 hours. Thermal hyperalgesia at day 3, but not at 6 hours, after CFA injection was blocked by intrathecal administration of anti-dynorphin antiserum or by bradykinin receptor antagonists. The antihyperalgesic effect of the latter was not due to de novo production of bradykinin or upregulation of spinal bradykinin receptors. These data suggest that elevated spinal dynorphin on peripheral inflammation mediates chronic inflammatory hyperalgesia. The antihyperalgesic effect of bradykinin receptor antagonists requires the presence of upregulated spinal dynorphin but not of de novo production of bradykinin, supporting our hypothesis that pathological levels of dynorphin may activate spinal bradykinin receptors to mediate inflammatory hyperalgesia.


CONCLUSIONS
This study shows that chronic peripheral inflammation induces a significant upregulation of the endogenous opioid peptide dynorphin. Elevated levels of spinal dynorphin and activation of spinal bradykinin receptors are essential to maintain inflammatory hyperalgesia. The results suggest that blockade of spinal bradykinin receptors may have therapeutic potential in chronic inflammatory pain.
Luo
Miaw-Chyi
MC
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
Chen
Qingmin
Q
Ossipov
Michael H
MH
Rankin
David R
DR
Porreca
Frank
F
Lai
Josephine
J
D000276:Adjuvants, Immunologic; D000704:Analysis of Variance; D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D004399:Dynorphins / Q000235:genetics* / Q000378:metabolism; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D007278:Injections, Spinal; D007609:Kallidin / Q000378:metabolism; D007704:Kininogens / Q000235:genetics; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D000276:Adjuvants, Immunologic; D007704:Kininogens; D012333:RNA, Messenger; D018002:Receptors, Bradykinin; D014316:Tritium; D007609:Kallidin; D004399:Dynorphins; D005620:Freund's Adjuvant; D001920:Bradykinin