ANTIBODY NOCICEPTOR SENSITIZATION AND ALLOYDNIA

点击翻译按钮获取中文摘要

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.