Robert R. Myers, PhD - US grants

2-chloroprocaine has enjoyed wide clinical usage for a variety of nerve block procedures because it has a rapid onset, short duration, and is quickly hydrolyzed by pseudocholinesterase circulating in the bloodstream. This, plus the fact that the fetus itself has the capability of rapidly hydrolyzing this drug, has made it particularly attractive for use in epidural anesthesia for obstetrics. Recent clinical reports, however, have suggested that under certain circumstances this drug may be neurotoxic to the parturient even in routine clinical concentrations. Attempts to study this potential toxicity in a variety of animal models have led to conflicting and controversial results. This study will directly observe the effect of 2-chloroprocaine and other local anesthetics on endoneurial fluid pressure, peripheral nerve ultrastructure, and nerve blood flow. Other substances known to produce peripheral neuropathies have been studied with these techniques and have shown the development of endoneurial edema with significantly elevated endoneurial fluid pressures. These changes were directly correlated with alterations in peripheral nerve ultrastructure. A decrease in nerve blood flow is a consequence of the elevated tissue pressure in the nerve. The animal model to be used will be the adult Sprague-Dawley rat which has had its sciatic nerve exposed on each side. One side will be injected with a 10 Mul volume of the test local anesthetic solution, while the other side will be bathed in the same solution. Endoneurial fluid pressure will be measured at various times from one hour through thirty days by utilizing a servo-null micropipette system, which is associated with minimal trauma. Morphometry will be studied fom electron micrographs of peripheral nerve to determine the distribution of nerve fibre diameters in control animals and in the animal preparations which have been exposed to the local anesthetics. Should the infusion or perfusion of the local anesthetic solution cause significant rises in endoneurial fluid pressure and/or pathologic changes, nerve blood flow will be measured utilizing techniques already developed in this laboratory.

Focal injury to peripheral nerve that leaves it intact can produce a painful hyperesthetic state referred to as neuropathic pain or causalgia. The mechanisms by which an acutely painful event can progress toward chronic pain are not known but there are certainly structural, physiologic, and biochemical changes in nerve that influence dorsal root ganglia and spinal cord neurons. The recent development of a non-neuroma rodent model of hyperesthesia is a major advance in pain research that can be used to elucidate the mechanisms of the hyperesthetic state. The model consists of the placement of loose ligatures around rat sciatic nerve and behavioral testing of hyperesthesia to heat or pressure applied to the affected foot pad. The hyperesthesia develops within 2 days, peaks at 5-7 days and resolves within one month. Preliminary studies reveal reductions in nerve blood flow associated with endoneurial edema and nerve fiber injury to small myelinated fibers. C fibers appear not to be severely affected, a finding consistent with our observation that capsaicin treatment does not affect the hyperesthesia to heat stimuli. Our preliminary work has also revealed that several different focal nerve injuries produce hyperesthesia to heat and mechanical stimuli including a pure ischemia model in which the epineurial circulation is removed from the surface of the nerve. The similarities in pathophysiology and in histological findings suggest a common pathogenic mechanism in which increased endoneurial fluid pressure and decreased nerve blood flow may be critical factors in the development of the hyperesthesia state. These experiments have also shown that blockade of retrograde axonal transport eliminates the hyperesthetic response to nerve compression and that the hyperesthetic state can be modified by pharmacological inhibition or excitation of different receptors on spinal cord neurons. Our working hypothesis is that focal nerve lesions resulting in increased endoneurial fluid pressure with local nerve ischemia cause morphological changes in nerve, increased peripheral afferent sensitivity, and trophic changes in spinal pathways that produce the hyperesthetic state. In this study we will explore these hypothesized mechanisms in five clinically relevant models of neuropathic pain, using physiological, behavioral, pharmacological, and histological methods. The results of these basic scientific studies should provide the rationale for pharmacological intervention in humans with neuropathic pain.

The Local Organizing Committee for the 1999 Meeting of the Peripheral Nerve Society is requesting support for the scientific activities of this international scientific meeting and funds for travel stipends to encourage participation by junior scholars beginning careers in peripheral nerve research. The scientific theme of the meeting is PAINFUL NEUROPATHIES. This theme was selected in part to encourage multidisciplinary interchange between clinicians exposed to this serious medical problem and basic scientists who have recently made significant strides in understanding the pathogenesis of chronic pain states arising after nerve injury and metabolic disease. For example, there is substantial new evidence that the basic mechanisms of nerve injury, degeneration, and regeneration are directly linked to different forms of pain, and that new understandings of these basic mechanisms might be translated to improved pain therapy. The meeting will be open to all registrants, many of which will be members of the Peripheral Nerve Society, the sponsoring organization. Abstracts on any aspect of the peripheral nervous system will be considered from any applicant. A scientific review committee will select abstracts for platform or poster presentation, or for rejection. Keynote lectures and small discussions are integral parts of the program. The PI seeks NIH funds for the following purposes: 1) Travel stipends for junior/trainee attendees, 2) facility and posterboard rental for scientific sessions, and 3) publication of abstracts. The majority of the funds requested will be used to support the attendance by junior investigators and students interested in the peripheral nervous system. Traditionally, these students were in the fields of neurology, neuropathology, and neurophysiology, but interest in the PNS is expanding and we expect to attract additionally from anesthesiology, orthopedics (spine surgery), and pharmacology. We offer the junior member a focused program of basic and clinical science in the peripheral nervous system and exposure to international experts in the field. We historically have selected retreat-like venues for Society meetings, as we believe this promotes the interaction and friendship that expands ones scientific career. We seek NIH support to further expand these opportunities for developing scientists and clinicians interested in the peripheral nervous system.