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. 2009 Mar 17;159(2):780-6.
doi: 10.1016/j.neuroscience.2008.12.049. Epub 2009 Jan 3.

Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican

Affiliations

Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican

O Bogen et al. Neuroscience. .

Abstract

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.

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Figures

Figure 1
Figure 1. MCP-1 induces mechanical hyperalgesia
(A) Dose-response curve for the effect of intradermal MCP-1 on mechanical nociceptive threshold following administration into the dorsum of the rat hind paw. Incremental doses from 100 pg to 1μg were administered at 30 min intervals. A one-way repeated measures ANOVA (5 different doses) showed a significant effect of dose [F(4,28) = 77.912, P
Figure 2
Figure 2. MCP-1 hyperalgesia is dependent on IB4 (+)-nociceptors
(A) MCP-1 but not NGF hyperalgesia was inhibited by intrathecal administration of IB4-saporin. A two-way ANOVA with two between subjects factors (intrathecal vehicle or IB4-saporin; and intradermal MCP-1 or NGF) showed a significant intrathecal × intradermal treatment interaction [F(1,20) = 144.882, P
Figure 3
Figure 3. MCP-1 hyperalgesia is dependent on versican
MCP-1 but not NGF hyperalgesia could be blocked by intrathecal administration of antisense oligodeoxynucleotides to versican mRNA. A two-way ANOVA with two between subjects factors (intrathecal antisense or mismatch ODNs; and intradermal MCP-1 or NGF) showed a significant intrathecal × intradermal treatment interaction [F(1,20) = 49.083, P
Figure 4
Figure 4. MCP-1 hyperalgesia is dependent on peripheral versican
MCP-1 but not NGF hyperalgesia could be blocked by intradermal administration of ADAMTS-4 or chondroitinase ABC, two enzymes that are known to affect versican integrity either by the degradation of the versican core-protein or its chondroitin sulfate glycosaminoglycan side chains. The effect of ADAMTS-4 and chondroitinase ABC on MCP-1- and NGF-induced hyperalgesia was examined using separate one-way ANOVAs with one between subjects factors with 3 different levels (vehicle, MCP-1, NGF). The groups receiving ADAMTS-4 or chondroitinase ABC demonstrated significant differences [F(2,21) = 99.478, P

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