Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican.
The type 1 chemokine monocyte chemoattractant protein (MCP-1) has been implicated in the generation of inflammatory and neuropathic pain, but the underlying mechanism remains poorly understood. Here we show that mechanical hyperalgesia induced by intradermal injection of MCP-1 in the rat is blocked by the intrathecal administration of isolectin B4 (IB4)-saporin, a selective neurotoxin for IB4(+)/Ret(+)-nociceptors. MCP-1-induced hyperalgesia is also attenuated by intrathecal antisense oligodeoxynucleotides targeting mRNA for versican, a molecule that binds MCP-1 and that also renders the Ret-expressing nociceptors IB4-positive (+). Finally, peripheral administration of ADAMTS-4 or chondroitinase ABC, two enzymes that disrupt versican integrity by the degradation of the versican core-protein or its chondroitin sulfate glycosaminoglycan side chains, respectively, also attenuated MCP-1 hyperalgesia at the site of nociceptive testing. We suggest that versican's glycosaminoglycan side chains present MCP-1 to a CCR2 expressing cell type in the skin that, in turn, selectively activates IB4(+)/Ret(+) nociceptors, thereby contributing to enhanced mechanical sensitivity under inflammatory conditions.
Bogen
O
O
Department of Medicine, Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA.
Dina
O A
OA
Gear
R W
RW
Levine
J D
JD
D051722:ADAM Proteins / Q000494:pharmacology; D000071121:ADAMTS4 Protein; D000704:Analysis of Variance; D000818:Animals; D018932:Chemokine CCL2; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D037102:Lectins / Q000627:therapeutic use; D008297:Male; D009498:Neurotoxins / Q000627:therapeutic use; D020320:Oligoribonucleotides, Antisense / Q000627:therapeutic use; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D011348:Procollagen N-Endopeptidase / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1 / Q000627:therapeutic use; D000076985:Saporins; D013997:Time Factors; D053675:Versicans / Q000235:genetics / Q000378:metabolism*
D018932:Chemokine CCL2; C496198:IB4-saporin conjugate; D037102:Lectins; D009498:Neurotoxins; D020320:Oligoribonucleotides, Antisense; D054789:Ribosome Inactivating Proteins, Type 1; D053675:Versicans; D000076985:Saporins; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; D019765:Chondroitin ABC Lyase