Integrin signaling in inflammatory and neuropathic pain in the rat.
Many painful conditions are associated with alterations in the extracellular matrix (ECM) of affected tissues. While several integrins, the receptors for ECM proteins, are present on sensory neurons that mediate pain, the possible role of these cell adhesion molecules in inflammatory or neuropathic pain has not been explored. We found that the intradermal injection of peptide fragments of domains of laminin and fibronectin important for adhesive signaling selectively inhibited the hyperalgesia caused by prostaglandin E2 (PGE2) and epinephrine (EPI), respectively. The block of EPI hyperalgesia was mimicked by other peptides containing the RGD integrin-binding sequence. Monoclonal antibodies (mAbs) against the alpha1 or alpha3 integrin subunits, which participate in laminin binding, selectively blocked PGE2 hyperalgesia, while a mAb against the alpha5 subunit, which participates in fibronectin binding, blocked only EPI-induced hyperalgesia. A mAb against the beta1 integrin subunit, common to receptors for both laminin and fibronectin, inhibited hyperalgesia caused by both agents, as did the knockdown of beta1 integrin expression by intrathecal injection of antisense oligodeoxynucleotides. The laminin peptide, but not the fibronectin peptides, also reversibly abolished the longer lasting inflammatory hyperalgesia induced by carrageenan. Finally, the neuropathic hyperalgesia caused by systemic administration of the cancer chemotherapy agent taxol was reversibly inhibited by antisense knockdown of beta1 integrin. These results strongly implicate specific integrins in the maintenance of inflammatory and neuropathic hyperalgesia.
Departments of Medicine and Oral and Maxillofacial Surgery, Division of Neuroscience and Biomedical Sciences Program, NIH Pain Center (UCSF), CA 94143-0440, USA.
Olayinka A
OA
Dina
Carlos A
CA
Parada
Jenny
J
Yeh
Xiaojie
X
Chen
Gordon C
GC
McCarter
Jon D
JD
Levine
D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002351:Carrageenan; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004837:Epinephrine; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010455:Peptides; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D021122:Protein Subunits / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016023:Integrins; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; D021122:Protein Subunits; D002351:Carrageenan; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D015232:Dinoprostone; D017239:Paclitaxel; D004837:Epinephrine