Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats.
Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes. Allodynia refers to pain in response to light touch/pressure stimuli, which normally are perceived as innocuous. Mirror-image allodynia arises from the healthy body region contralateral to the actual site of trauma/inflammation. Virtually nothing is known about the mechanisms underlying such pain. A recently developed animal model of inflammatory neuropathy reliably produces mirror-image allodynia, thus allowing this pain phenomenon to be analyzed. In this sciatic inflammatory neuropathy (SIN) model, decreased response threshold to tactile stimuli (mechanical allodynia) develops in rats after microinjection of immune activators around one healthy sciatic nerve at mid-thigh level. Low level immune activation produces unilateral allodynia ipsilateral to the site of sciatic inflammation; more intense immune activation produces bilateral (ipsilateral + mirror image) allodynia. The present studies demonstrate that both ipsilateral and mirror-image SIN-induced allodynias are (1) reversed by intrathecal (peri-spinal) delivery of fluorocitrate, a glial metabolic inhibitor; (2) prevented and reversed by intrathecal CNI-1493, an inhibitor of p38 mitogen-activated kinases implicated in proinflammatory cytokine production and signaling; and (3) prevented or reversed by intrathecal proinflammatory cytokine antagonists specific for interleukin-1, tumor necrosis factor, or interleukin-6. Reversal of ipsilateral and mirror-image allodynias was rapid and complete even when SIN was maintained constantly for 2 weeks before proinflammatory cytokine antagonist administration. These results provide the first evidence that ipsilateral and mirror-image inflammatory neuropathy pain are created both acutely and chronically through glial and proinflammatory cytokine actions.
Milligan
Erin D
ED
Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309-0345, USA.
Twining
Carin
C
Chacur
Marucia
M
Biedenkapp
Joseph
J
O'Connor
Kevin
K
Poole
Stephen
S
Tracey
Kevin
K
Martin
David
D
Maier
Steven F
SF
Watkins
Linda R
LR
D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000906:Antibodies / Q000008:administration & dosage; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000008:administration & dosage; D002951:Citrates / Q000008:administration & dosage; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006835:Hydrazones / Q000008:administration & dosage; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D007278:Injections, Spinal; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D020426:Sciatic Neuropathy / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D012795:Sialoglycoproteins / Q000008:administration & dosage; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D053319:Tumor Necrosis Factor Decoy Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; D000813:Anilides; D006146:Guanidines
D000154:Aconitate Hydratase; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D002352:Carrier Proteins; D002951:Citrates; D016207:Cytokines; D004791:Enzyme Inhibitors; D006835:Hydrazones; D053590:Interleukin 1 Receptor Antagonist Protein; D020928:Mitogen-Activated Protein Kinases; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins; D053319:Tumor Necrosis Factor Decoy Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C069521:recombinant human tumor necrosis factor-binding protein-1; C007744:fluorocitrate; C097256:semapimod; D000813:Anilides; D006146:Guanidines