Recent observations suggest that antibody-antigen reactions along sensory axons, such as occurs following recognition of the anti-GD2 antibody for it membrane constituent antigen, may lead to complement fixation and an associated local release of tumor necrosis factor-a (TNF) from mast cells and Schwann cells. TNF forms membrane na+ pores providing a novel mechanism for initiating ectopic depolarization of axons at non terminal sites. This alteration in sensory processing is independent of peripheral receptors or structural changes of the axon. Systemic administration of antiGD2, as an immunotherapeutic agent, leads to severe pain and allodynia in man. Thia allodynia can be modeled in rats: administration of anti-GD2 antibody results in ongoing activity in afferent fibers as well as nociceptor sensitization. Endogenous TNF is released within nerves in many pain states, including local inflammation and injury. focal administration of TNF to the nerve trunk also elicits discharge in nociceptive afferents at frequencies consistent with the development of central sensitization. This proposal will investigate the hypothesis that anitGD2 antibody alterations of nociception are induced by an immune response initiated case along the peripheral nociceptive axons. Behavioral responses of rats treated with anti-GD2 to a range of cutaneous stimuli will be measured. Mechano-allodynia and thermal hyperalgesia will be tested. Dependence of the pan state on complement fixation, prostanoids and cytokine release will be explored. Ongoing activity and sensory thresholds will be recorded for identified primary afferent fibers, concentrating on A and C fibers thought to transmit pain information. Manipulations of the same variables used to examine generation of behavioral pain states will be used as pretreatments before recording excitability of nerve fibers. In this way, parallel changes between pain behavior and electrophysiology will be assessed. TNF, prostanoids and local increases in acidity will be administered directly to the nerve trunk to ascertain if these substances are sufficient to trigger the cascade. Results will begin to delineate the pharmacological sequence of events by which administration of GD2 antibody produces pain. This work will be the first step in determining if mid axonal generation of increased afferent throughput, mediated by TNF, is a common element in pathological pain states associated with tissue and nerve injury. This series of events along the axon represents a fundamentally different way for explaining the generation of many anomalous pain states and may thus initiate development of novel approaches to treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035630-03
Application #
2873206
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Kitt, Cheryl A
Project Start
1997-04-01
Project End
2001-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Schafers, Maria; Marziniak, Martin; Sorkin, Linda S et al. (2004) Cyclooxygenase inhibition in nerve-injury- and TNF-induced hyperalgesia in the rat. Exp Neurol 185:160-8
Schafers, Maria; Sorkin, Linda S; Sommer, Claudia (2003) Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats. Pain 104:579-88
Schafers, M; Sorkin, L S; Geis, C et al. (2003) Spinal nerve ligation induces transient upregulation of tumor necrosis factor receptors 1 and 2 in injured and adjacent uninjured dorsal root ganglia in the rat. Neurosci Lett 347:179-82
Portbury, Andrea L; Chandra, Rashmi; Groelle, Marybeth et al. (2003) Catecholamines act via a beta-adrenergic receptor to maintain fetal heart rate and survival. Am J Physiol Heart Circ Physiol 284:H2069-77
Schafers, Maria; Lee, Doo H; Brors, Dominik et al. (2003) Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J Neurosci 23:3028-38
Schafers, Maria; Svensson, Camilla I; Sommer, Claudia et al. (2003) Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 23:2517-21
Junger, Heidi; Moore, Alan C; Sorkin, Linda S (2002) Effects of full-thickness burns on nociceptor sensitization in anesthetized rats. Burns 28:772-7
Sorkin, L S; Yu, A L; Junger, H et al. (2002) Antibody directed against GD(2) produces mechanical allodynia, but not thermal hyperalgesia when administered systemically or intrathecally despite its dependence on capsaicin sensitive afferents. Brain Res 930:67-74
Sorkin, L S; Yaksh, T L; Doom, C M (2001) Pain models display differential sensitivity to Ca2+-permeable non-NMDA glutamate receptor antagonists. Anesthesiology 95:965-73
Luo, Z D; Chaplan, S R; Higuera, E S et al. (2001) Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci 21:1868-75

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