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ANALGESIA

Memory of Pain: The Effect of Perineural Resiniferatoxin

Igor Kissin, MD, PhD^*, Cristina F. Freitas, BA^*, and Edwin L. Bradley, Jr, PhD

From the *Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Biostatistics, University of Alabama at Birmingham.

Address correspondence and reprint requests to Igor Kissin, MD, PhD, Pain Research Center, Brigham and Women's Hospital, 75 Francis St., MRB611, Boston, MA 02115. Address e-mail to kissin{at}zeus.bwh.harvard.edu.

Abstract

The long-lasting imprint of acute pain in the central nervous system may contribute to the transition of acute pain to chronicity. The long-term potentiation (which is proposed as a mechanism of memory) and central sensitization were each reported as a form of synaptic plasticity, and both can be initiated by stimulation of C fibers. In the current study, we assessed nociceptive memory regarding hyperalgesia by measuring distant hyperalgesia after repeated carrageenan-induced inflammation. This approach was used to determine whether selective blockade of C fibers can prevent the development of a long-lasting imprint of hyperalgesia. In rat experiments, resiniferatoxin was administered percutaneously at the sciatic and saphenous nerves, and two crossover intraplantar injections of carrageenan into the hindpaws were performed 2 wk apart. Responses to noxious pressure and heat and changes in paw volumes were measured at various intervals during two carrageenan-induced inflammations. The experiments demonstrated that after recovery of hyperalgesia induced by the initial inflammation, repeated inflammation led to the development of a distant hyperalgesia that was absent during the initial inflammation. The maximum of distant hyperalgesia (decrease of noxious pressure threshold in the contralateral hindpaw from 141 ± 23 g to 96 ± 19 g; P < 0.0001) was reached 24 h after the second injection of carrageenan. The development of distant hyperalgesia during the repeated inflammation was completely prevented (P < 0.0002) by perineural resiniferatoxin (0.001%) administered before the initial injection of carrageenan. These results indicate that selective blockade of nociceptive fibers prevents formation of long-term hyperalgesia-related imprint in the central nervous system. Thus, pain memory can be preempted by selective and prolonged blockade of C-fibers.

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