Periganglionic inflammation elicits a distally radiating pain hypersensitivity by promoting COX-2 induction in the dorsal root ganglion.
We have developed a model in which inflammation contiguous to and within a dorsal root ganglion (DRG) was generated by local application of complete Freund's adjuvant (CFA) to the L4 lumbar spinal nerve as it exits from the intervertebral foramen. The periganglionic inflammation (PGI) elicited a marked reduction in withdrawal threshold to mechanical stimuli and an increase in heat pain sensitivity in the ipsilateral hindpaw in the absence of any hindpaw inflammation. The pain sensitivity appeared within hours and lasted for a week. The PGI also induced a prominent increase in IL-1beta and TNF-alpha levels in the DRG and of cyclooxygenase-2 (COX-2) expression in neurons and satellite cells. A selective COX-2 inhibitor reduced the PGI-induced hyperalgesia. We also show that IL-1beta induces COX-2 expression and prostaglandin release in DRG neurons in vitro in a MAP kinase-dependent fashion. The COX-2 induction was prevented by ERK and p38 inhibitors. We conclude that periganglionic inflammation increases cytokine levels, including IL-1beta, leading to the transcription of COX-2 and prostaglandin production in the affected DRG, and thereby to the development of a dermatomally distributed pain hypersensitivity.
Amaya
Fumimasa
F
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, USA.
Samad
Tarek A
TA
Barrett
Lee
L
Broom
Daniel C
DC
Woolf
Clifford J
CJ
D000704:Analysis of Variance; D000818:Animals; D001339:Autonomic Fibers, Preganglionic / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D001703:Biophysics; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005620:Freund's Adjuvant / Q000009:adverse effects; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000209:etiology*; D066298:In Vitro Techniques; D007249:Inflammation / Q000150:complications*; D007783:Lactones / Q000494:pharmacology; D008297:Male; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012585:Sciatica / Q000150:complications; D013450:Sulfones / Q000494:pharmacology
D016207:Cytokines; D004791:Enzyme Inhibitors; D007783:Lactones; D012333:RNA, Messenger; D013450:Sulfones; C116926:rofecoxib; D005620:Freund's Adjuvant; D051546:Cyclooxygenase 2