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Role of the nervi nervorum in neuropathic pain
Commentary
Role of the Nervi Nervorum in Neuropathic Pain Innocent Until Proven Guilty Linda S. Sorkin, * Rochelle Wagner, * and Robert R. Myers*t
octors Sove and Light present an important and interesting hypothesis on the function of unmyelinated sensory fibers with "free endings" in the perineurium. They suggest that these nociceptive fibers of the nervi nervorum serve an integral and unique role in the pathogenesis of neuropathic pain by signaling pain from direct stimulation and by initiating and reinforcing the electrophysiologic events that characterize the neuropathic pain state. Their hypothesis is based on several of their own observations and a substantial literature on the anatomy, function, and chemical sensitivity of nerve fibers. As the authors point out, the hypothesis has been expressed in slightly different forms in the past, but has not been formally tested. It extends a more fundamental hypothesis suggesting that the primary role of the nervi nerverum is to guard the fascicular axons from physical injury by nociceptive signaling and to help regulate the endoneurial environment through the release of neuropeptides that alter the blood-nerve barrier. That the nervi nervorum may contribute directly to the pathogenesis of neuropathic pain is an appealing hypothesis, but one that is difficult to test given the technical problems of isolating perineurial fibers and stimulating them without affecting the very large number of adjacent somatic fibers in the fascicular endoneurial space. To think that compression of the perineurium or chemical alterations in its environment could cause aberrant firing in the terminal receptors of the nervi ner-
D
From the *Department of Anesthesiology, and tDepartment of Pathology (Neuropathology), University of California, San Diego, School of Medicine, and tResearch Service, VA Medical Center, San Diego, La Jolla, CA. Reprint requests: Robert R. Myers, PhD, Department of Anesthesiology (0629), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0629.
Pain Forum 6(3): 191-192, 1997
vorum is certainly reasonable. We agree with the authors and, in fact, have proposed that stretching of the perineurium by increased endoneurial fluid pressure secondary to accumulation of endoneurial edema in the dorsal root ganglia or nerve could be painful [3]. This hypothesis is also supported by a vast literature on the neuropathologic and sensory abnormalities arising from external nerve compression. We, however, have argued that the principal pathogenic mechanism for neuropathologic injury and nociceptive behaviors in compression and chronic constriction injuries is ischemic injury to endoneurial nerve fibers [4,6,7] and that the painful neuropathic manifestations are due in part to the local actions of tumor necrosis factor (TNF) on the injured endoneurial fibers [9-11]. Importantly, these general mechanisms are invoked in the Focus article in the context of injury to the nervi nervorum, which are unavoidably perturbed in the nerve injuries we have studied [8]. It remains to be demonstrated that isolated injury to the nervi nervorum is sufficient to initiate the cascade of central events that lead to neuropathic pain states. In this context, it would be important for the authors to determine the density of the nervi nervorum and plan for their exclusive injury. Several observations from our work would seemingly suggest that a critical number of nerve fibers need to be injured before there is significant development of hyperalgesia. In studies in which a cryogenic probe was applied to the surface of rat sciatic nerves, we observed that both the magnitude and duration of the resulting hyperalgesia were directly related to the number of endoneurial fibers injured by the freeze lesion [5]. The perineurium and presumably the nervi nervorum were injured by every freeze lesion, but as the duration of the freeze insult increased, the pathologic changes progressed from the perineurium inward to involve more fibers in the fascicle. If only injury to the nervi nervorum
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fibers were important in the pathogenesis of neuropathic pain, then injury to the fascicular contents would not be so highly correlated to the severity of the pain state. In other studies in which the epineurial vasculature was removed from a 2-cm-long segment of nerve, there was only mild hyperalgesia associated with injuries to a small subset of fascicular fibers in the subperineurial space [6]. More extensive ischemia causes an increase in the number of injured fibers and greater hyperalgesia. Presumably, nervi nervorum fibers were injured by removing the epineurial vasculature, but we did not focus on perineurial pathologic changes. We are in complete agreement with the importance of the chemical environment of nerve fibers, especially chemical changes evoked by local inflammation, trauma, and immune reactions, in the etiology of neuropathic pain. Endoneurial injection of TNF or its second messenger ceramide in the sciatic nerve results in allodynia and/or hyperalgesia comparable to that seen following chronic constriction injury to the same area of the nerve trunk [11]. Interestingly, the neuropathologic changes observed in TNF-injected tissue mimicked those seen in a number of other painful inflammatory neuropathies and included activation of TNF-producing Schwann cells, blebbing and disintegration of the myelin sheath, and invasion of macrophages into the endoneurial space. Rather than focus on the chemosensitivity of the nerve endings within the nerve sheath and vasculature, we believe that chemical changes in the perineural milieu elicit activity from the axons of passage. Recent findings from our group [9] indicate that local administration of physiologic concentrations of TNF to the sciatic nerve trunk in vivo initiates background discharge in nociceptive afferent fibers with cutaneous receptive fields on the paw. Following application of the cytokine, an overwhelming majority of Adelta and C nociceptors started to fire in bursts of up to 9 Hz, with C fibers being the more reactive. As fibers of the nervi nervorum do not have distant cutaneous receptive fields (1), this implies that the observed activity was not initiated via the mechanism described in the Focus article. Endogenous TNF could be released from Schwann cells subsequent to injury or inflammation [10], or it could come from endoneurial mast cells, fibroblasts, and invading macrophages. As TNF is itself proinflammatory and causes further degranulation of mast cells, other mast cell contents could participate in the generation of midaxonal activity in clinical situations as well as in our experiments. Recently, it has been shown that mast cells store and release nerve growth factor [2] and interleukins, in addition to the more well-known contents such as histamine, serotonin, and chemotactic
factors. Interestingly, interleukin-3 causes increased responsiveness of basophils to complement component C3a, implicating this system as a player in neuropathic pain associated with some autoimmune disorders. Thus, a new brand of endogenous inflammatory soup acting midaxonally, rather than at the receptor ending, is independently capable of generating the ectopic activity important in the pathogenesis of neuropathic pain. Electrophysiologic activity of endoneurial C fibers may be sufficient to cause referred pain in the skin and potentially could elicit central changes leading to neuropathic pain states independent of nociceptor activation in the nervi nervorum. It may not be necessary for the free nerve endings of the nervi nervorum to be activated by local injury or inflammation to result in neuropathic pain; however, the two mechanisms may work in concert to elicit the full spectrum of pain associated with nerve injury.
References 1. Sove GM, Light AR: Unmyelinated nociceptors of rat paraspinal tissues. J Neurophysiol 73: 1752-1762, 1995 2. Leon A, Suriani A, Dal Toso R et al. Mast cells synthesize, store and release nerve growth factor. Proc Natl Acad Sci USA 91:3739-3743,1994 3. Lundborg G, Myers R, Powell H: Nerve compression injury and increased endoneurial fluid pressure: a "miniature compartment syndrome." J Neurol Neurosurg Psychiatry 46: 1119-1124, 1983. 4. Myers RR: The pathogenesis of neuropathic pain. Reg. Anesth 20: 173-184, 1995 5. Myers RR, Heckman HM, Powell HC: Axonal viability and the persistence of thermal hyperalgesia after partial freeze lesions of nerve. J Neurol Sci 139:28-38, 1996 6. Myers RR, YamamotoT, Yaksh TL, Powell HC: The role of focal nerve ischemia and Wallerian degeneration in peripheral nerve injury producing hyperesthesia. Anesthesiology 78:308-316, 1993 7. Powell HC, Myers RR: Pathology of experimental nerve compression. Lab Invest 55:91-100, 1986 8. Sommer C, Galbraith JA, Heckman HM, Myers RR: Pathology of experimental compression neuropathy producing hyperesthesia. J Neuropathol Exp Neurol 52:223-233, 1993 9. Sorkin LS, Xiao W-H, Wagner R, Myers RR: Tumor necrosis factor-a induces ectopic activity in nociceptive primary afferent fibers. Neuroscience 81 :255-262, 1997 10. Wagner R, Myers RR: Schwann cells produce tumor necrosis factor alpha: expression in injured and noninjured nerves. Neuroscience 73:625-629, 1996 11. Wagner R, Myers RR: Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. NeuroReport 7:2897-2901, 1996
Role of the Nervi Nervorum in Neuropathic Pain Innocent Until Proven Guilty Linda S. Sorkin, * Rochelle Wagner, * and Robert R. Myers*t
octors Sove and Light present an important and interesting hypothesis on the function of unmyelinated sensory fibers with "free endings" in the perineurium. They suggest that these nociceptive fibers of the nervi nervorum serve an integral and unique role in the pathogenesis of neuropathic pain by signaling pain from direct stimulation and by initiating and reinforcing the electrophysiologic events that characterize the neuropathic pain state. Their hypothesis is based on several of their own observations and a substantial literature on the anatomy, function, and chemical sensitivity of nerve fibers. As the authors point out, the hypothesis has been expressed in slightly different forms in the past, but has not been formally tested. It extends a more fundamental hypothesis suggesting that the primary role of the nervi nerverum is to guard the fascicular axons from physical injury by nociceptive signaling and to help regulate the endoneurial environment through the release of neuropeptides that alter the blood-nerve barrier. That the nervi nervorum may contribute directly to the pathogenesis of neuropathic pain is an appealing hypothesis, but one that is difficult to test given the technical problems of isolating perineurial fibers and stimulating them without affecting the very large number of adjacent somatic fibers in the fascicular endoneurial space. To think that compression of the perineurium or chemical alterations in its environment could cause aberrant firing in the terminal receptors of the nervi ner-
D
From the *Department of Anesthesiology, and tDepartment of Pathology (Neuropathology), University of California, San Diego, School of Medicine, and tResearch Service, VA Medical Center, San Diego, La Jolla, CA. Reprint requests: Robert R. Myers, PhD, Department of Anesthesiology (0629), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0629.
Pain Forum 6(3): 191-192, 1997
vorum is certainly reasonable. We agree with the authors and, in fact, have proposed that stretching of the perineurium by increased endoneurial fluid pressure secondary to accumulation of endoneurial edema in the dorsal root ganglia or nerve could be painful [3]. This hypothesis is also supported by a vast literature on the neuropathologic and sensory abnormalities arising from external nerve compression. We, however, have argued that the principal pathogenic mechanism for neuropathologic injury and nociceptive behaviors in compression and chronic constriction injuries is ischemic injury to endoneurial nerve fibers [4,6,7] and that the painful neuropathic manifestations are due in part to the local actions of tumor necrosis factor (TNF) on the injured endoneurial fibers [9-11]. Importantly, these general mechanisms are invoked in the Focus article in the context of injury to the nervi nervorum, which are unavoidably perturbed in the nerve injuries we have studied [8]. It remains to be demonstrated that isolated injury to the nervi nervorum is sufficient to initiate the cascade of central events that lead to neuropathic pain states. In this context, it would be important for the authors to determine the density of the nervi nervorum and plan for their exclusive injury. Several observations from our work would seemingly suggest that a critical number of nerve fibers need to be injured before there is significant development of hyperalgesia. In studies in which a cryogenic probe was applied to the surface of rat sciatic nerves, we observed that both the magnitude and duration of the resulting hyperalgesia were directly related to the number of endoneurial fibers injured by the freeze lesion [5]. The perineurium and presumably the nervi nervorum were injured by every freeze lesion, but as the duration of the freeze insult increased, the pathologic changes progressed from the perineurium inward to involve more fibers in the fascicle. If only injury to the nervi nervorum
191
192
COMMENTARY/Sorkin et al.
fibers were important in the pathogenesis of neuropathic pain, then injury to the fascicular contents would not be so highly correlated to the severity of the pain state. In other studies in which the epineurial vasculature was removed from a 2-cm-long segment of nerve, there was only mild hyperalgesia associated with injuries to a small subset of fascicular fibers in the subperineurial space [6]. More extensive ischemia causes an increase in the number of injured fibers and greater hyperalgesia. Presumably, nervi nervorum fibers were injured by removing the epineurial vasculature, but we did not focus on perineurial pathologic changes. We are in complete agreement with the importance of the chemical environment of nerve fibers, especially chemical changes evoked by local inflammation, trauma, and immune reactions, in the etiology of neuropathic pain. Endoneurial injection of TNF or its second messenger ceramide in the sciatic nerve results in allodynia and/or hyperalgesia comparable to that seen following chronic constriction injury to the same area of the nerve trunk [11]. Interestingly, the neuropathologic changes observed in TNF-injected tissue mimicked those seen in a number of other painful inflammatory neuropathies and included activation of TNF-producing Schwann cells, blebbing and disintegration of the myelin sheath, and invasion of macrophages into the endoneurial space. Rather than focus on the chemosensitivity of the nerve endings within the nerve sheath and vasculature, we believe that chemical changes in the perineural milieu elicit activity from the axons of passage. Recent findings from our group [9] indicate that local administration of physiologic concentrations of TNF to the sciatic nerve trunk in vivo initiates background discharge in nociceptive afferent fibers with cutaneous receptive fields on the paw. Following application of the cytokine, an overwhelming majority of Adelta and C nociceptors started to fire in bursts of up to 9 Hz, with C fibers being the more reactive. As fibers of the nervi nervorum do not have distant cutaneous receptive fields (1), this implies that the observed activity was not initiated via the mechanism described in the Focus article. Endogenous TNF could be released from Schwann cells subsequent to injury or inflammation [10], or it could come from endoneurial mast cells, fibroblasts, and invading macrophages. As TNF is itself proinflammatory and causes further degranulation of mast cells, other mast cell contents could participate in the generation of midaxonal activity in clinical situations as well as in our experiments. Recently, it has been shown that mast cells store and release nerve growth factor [2] and interleukins, in addition to the more well-known contents such as histamine, serotonin, and chemotactic
factors. Interestingly, interleukin-3 causes increased responsiveness of basophils to complement component C3a, implicating this system as a player in neuropathic pain associated with some autoimmune disorders. Thus, a new brand of endogenous inflammatory soup acting midaxonally, rather than at the receptor ending, is independently capable of generating the ectopic activity important in the pathogenesis of neuropathic pain. Electrophysiologic activity of endoneurial C fibers may be sufficient to cause referred pain in the skin and potentially could elicit central changes leading to neuropathic pain states independent of nociceptor activation in the nervi nervorum. It may not be necessary for the free nerve endings of the nervi nervorum to be activated by local injury or inflammation to result in neuropathic pain; however, the two mechanisms may work in concert to elicit the full spectrum of pain associated with nerve injury.
References 1. Sove GM, Light AR: Unmyelinated nociceptors of rat paraspinal tissues. J Neurophysiol 73: 1752-1762, 1995 2. Leon A, Suriani A, Dal Toso R et al. Mast cells synthesize, store and release nerve growth factor. Proc Natl Acad Sci USA 91:3739-3743,1994 3. Lundborg G, Myers R, Powell H: Nerve compression injury and increased endoneurial fluid pressure: a "miniature compartment syndrome." J Neurol Neurosurg Psychiatry 46: 1119-1124, 1983. 4. Myers RR: The pathogenesis of neuropathic pain. Reg. Anesth 20: 173-184, 1995 5. Myers RR, Heckman HM, Powell HC: Axonal viability and the persistence of thermal hyperalgesia after partial freeze lesions of nerve. J Neurol Sci 139:28-38, 1996 6. Myers RR, YamamotoT, Yaksh TL, Powell HC: The role of focal nerve ischemia and Wallerian degeneration in peripheral nerve injury producing hyperesthesia. Anesthesiology 78:308-316, 1993 7. Powell HC, Myers RR: Pathology of experimental nerve compression. Lab Invest 55:91-100, 1986 8. Sommer C, Galbraith JA, Heckman HM, Myers RR: Pathology of experimental compression neuropathy producing hyperesthesia. J Neuropathol Exp Neurol 52:223-233, 1993 9. Sorkin LS, Xiao W-H, Wagner R, Myers RR: Tumor necrosis factor-a induces ectopic activity in nociceptive primary afferent fibers. Neuroscience 81 :255-262, 1997 10. Wagner R, Myers RR: Schwann cells produce tumor necrosis factor alpha: expression in injured and noninjured nerves. Neuroscience 73:625-629, 1996 11. Wagner R, Myers RR: Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. NeuroReport 7:2897-2901, 1996