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An alternative mechanism for neuropathic pain
Commentary
An Alternative Mechanism for Neuropathic Pain Nervi Nervorum William D. Willis, Jr.
he Focus article by Doctors Sove and Light calls attention to the generally neglected innervation of nerve sheaths, the nervi nervorum . It is asserted that the hypotheses that were proposed during the last century concerning the diagnosis and treatment of neuropathic and musculoskeletal pain have failed to withstand scientific scrutiny and that the nervi nervorum may be at least one of the "offending agents" that cause neuropathic pain. The Focus article gives a historical review of what is known about the nervi nervorum (including in this category the nervi vasorum nervorum , the nerve fibers that supply the blood vessels within the nerve sheath). They are chiefly unmyelinated axons havinq "free endings" (although some have encapsulated endings) in the layers of connective tissue about peripheral nerves [13], and many of these axons contain neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP) [2,6]. The authors have recently shown that at least some nervi nervorum in the deep paraspinal tissues are nociceptors [7]. The nervi nervorum afferents have multiple, punctate receptive fields and respond to noxious mechanical, chemical , and thermal stimuli. Interestingly, they can also have receptive fields in adjacent muscles or tendons. The authors agree with Asbury and Fields [3] that the nervi nervorum contribute to nerve trunk pain. Damage to a peripheral nerve or application of capsaicin results in hyperemia as a result of the release of SP and CGRP from the nervi nervorum [26,27]. The hyperemia can be prevented by local administration of a
T
From the Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston, TX. Reprint requests: William D. Willis , Jr., MD, Department of Anatomy and Neurosciences, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1069.
Pain Forum 6(3): 193-195, 1997
CGRP antagonist or by depletion of peptides by a previous application of capsaicin [14,27,28]. The authors therefore suggest that the nervi nervorum contribute to inflammation of peripheral nerve. The authors review the structure of the connective tissue layers of peripheral nerves and the effects of mechanical events that cause nerves to be stretched or compressed, as in the carpal tunnel syndrome. Mechanical forces applied to a nerve can activate nociceptors of the nervi nervorum or, if severe, inactivate them. If activated, the nerve fibers can contribute to neurogenic inflammation and pain [24]. A widely used model of neuropathic pain is produced by loose ligation of the sciatic nerves in rats [5]. Several studies point to a role for inflammation in the pain state seen in this model [10,21]. In fact, the pain state can be produced by aligning chromic gut sutures with the sciatic nerve without actually ligating the nerve [18] (however, see also Ref. [21D. Regeneration of damaged nervi nervorum could lead to the formation of a "miniature neuroma-in-continuity" around the nerve. Eventually, scar tissue might form in the epineurium, leading to "chronic friction injury to the nerve," afferent activity if the scar is innervated, and constriction of the nerve. Axonal sprouts grow into damaged nerve [4]; these "secondary" nervi nervorum contribute to the sensitivity of the nerve to mechanical stimuli. They are not branches of the original nervi nervorum , as they have cutaneous receptive fields, unlike the primary nervi nervorum. The formation of adhesions would further complicate the picture. The receptive fields of nervi nervorum in other tissues would help explain the spread of tenderness beyond the site of injury. Although central nervous system changes, such as central sensitization , contribute to chronic pain, maintenance of such changes depends on continual peripheral input from nociceptors. If this input ceases, central
193
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sensitization disappears within hours [12,23,25]. The peripheral input has been attributed to ectopic discharges from axonal sprouts in neuromas and from dorsal root ganglion cells [1,15]. Bove and Light hypothesize that a major contributor to this continual peripheral nociceptive input arises from the nervi nervorum.
EVIDENCE IN SUPPORT OFTHE NERVI NERVORUM HYPOTHESIS OF SOVE AND LIGHT Evidence in favor of the hypothesis that inflammation of a nerve involving the nervi nervorum contributes to neuropathic pain is that dexamethasone reduces the inflammation of the nerve and the severity of the pain state in the Bennett and Xie model [10]. Several experiments done by the Galveston group on the Bennett and Xie model of neuropathic pain are also consistent with the hypothesis of Bove and Light. Following loose ligations of the sciatic nerve, a neuroma was found to form on the nerve [8] (see also Ref. [21]). Part of the neuroma was undoubtedly formed by sprouting axons of the nerve trunk; however, part could have been formed as a "neuroma-in-continuity" of the nervi nervorum, as suggested by Bove and Light. When the sciatic nerve was pretreated with lidocaine in the Bennett and Xie model [11], the severity of the pain state was reduced and the pain state was shortened in duration, whereas lidocaine did not alter the pain state produced in the model of neuropathic pain developed by Seltzer et al. [22]. It is difficult to explain this observation based on the duration of action of lidocaine and the assumption that the pain state depends on the initial input from compressed axons. Another interpretation would be that the lidocaine helped minimize peptide release from the nervi nervorum and thus reduced the amount of inflammation of the sciatic nerve in the Bennett and Xie model. The Seltzer et al. model involves tight ligation of the sciatic nerve, which would be associated with a transient injury discharge. Presumably, rather than being maintained by a progressive inflammation of the nerve, the pain state appears to be maintained by ectopic discharges from the dorsal root ganglion. Similarly, in the model of neuropathic pain developed by Kim and Chung [16], one or two spinal nerves are tightly ligated. This would presumably have an effect similar to that of tight ligation of part of the sciatic nerve in the Seltzer et al. model. Ectopic discharges from dorsal root ganglion cells also appear to contribute to the continuous peripheral input that causes central sensitization in the Kim and Chung model; however, in both the Seltzer et al. and Kim and Chung models, inflammation and eventual scarring could also occur, and so it is plausible that discharges would also originate from damaged and regen-
erating nervi nervorum. Maintained peripheral input is known to be required in the model of Kim and Chung to support central sensitization, as the allodynia and hyperalgesia diminish rapidly after the dorsal roots of the ligated segments are sectioned [23,25]; however, dorsal rhizotomy would interfere with discharges originating from the dorsal root ganglion, from a neuroma in the spinal nerve, and from a neuroma involving nervi nervorum.
EVIDENCE THAT IS NOT CONSISTENT WITH THE HYPOTHESIS In many cases of neuropathic pain, including the Kim and Chung model, the pain is sympathetically maintained [17]. The nervi nervorum hypothesis does not address this issue. One explanation for a role of the sympathetic nervous system in maintaining the pain state in the model developed by Kim and Chung is the ingrowth of sympathetic nerve fibers into the dorsal root ganglion in the ligated segments [9]. These sympathetic axons, recognized by their content of tyrosine hydroxylase, form whorls around dorsal root ganglion cells. A similar ingrowth of sympathetic axons also follows a complete transection of the sciatic nerve, although at a much later time [19]. Stimulation of the sympathetic trunk, in such preparations, has been shown to excite dorsal root ganglion cells [20]. There is no reason to implicate the nervi nervorum in this process. Furthermore, most of the pain state in the Kim and Chung model is alleviated by sympathectomy [17J, and so the contribution of the nervi nervorum appears to be minimal in this model of neuropathic pain.
References 1. Amir R, Devor M: Ongoing activity in neuroma afferents bearing retrograde sprouts. Brain Res 630:283-288, 1993 2. Appenzeller 0, Dhital KK, Cowen T, Burnstock G: The nerves to blood vessels supplying nerves: the innervation of vasa nervorum. Brain Res 304:383-386, 1984 3. Asbury AK, Fields HL: Pain due to peripheral nerve damage: an hypothesis. Neurology 34:1587-1590,1984 4. Bennett GJ: An animal model of neuropathic pain: a review. Muscle Nerve 16:1040-1 048, 1993 5. Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87-107,1988 6. Bove GM, Light AR: Calcitonin gene-related peptide and peripherin immunoreactivity in nerve sheaths. Somatosens Mot Res 12:49-57, 1995 7. Bove GM, Light AR: Unmyelinated nociceptors of rat paraspinal tissues. J NeurophysioI73:1752-1762, 1995 8. Carlton SM, Dougherty PM, Pover CM, Coggeshall RE: Neuroma formation and numbers ofaxons in a rat model
COMMENTARY/willis
9.
10.
11.
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13.
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of experimental peripheral neuropathy. Neurosci Lett 131:88-92,1991 Chung K, Lee BH, Yoon YW, Chung JM: Sympathetic sprouting in the dorsal root ganglia of the injured peripheral nerve in a rat neuropathic pain model. J Comp Neurol 376:241-252, 1996 Clatworthy AL, lilich PA, Castro GA, Walters ET: Role of peri-axonal inflammation in the development of thermal hyperalgesia and guarding behavior in a rat model of neuropathic pain. Neurosci Lett 184:5-8, 1995 Dougherty PM, Garrison CJ, Carlton SM: Differential influence of local anesthetic upon two models of experimentally induced peripheral mononeuropathy in the rat. Brain Res 570:109-115, 1992 Gracely RH, Lynch SA, Bennett GJ: Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 51:175-194, 1992 Hromada J: On the nerve supply of the connective tissue of some peripheral nervous tissue system components. Acta Anat 55:343-351, 1963 Jansco N, Jansco-Gabor A, Szolcsanyi J: Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol Chemother31:138-151, 1967 Kajander KC, Wakisaka S, Bennett GJ: Spontaneous discharge originates in the dorsal root ganglion at the onset of a painful peripheral neuropathy in the rat. Neurosci Lett 138:225-228, 1992 Kim SH, Chung JM: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355-363, 1992 Kim SH, Na HS, Sheen K, Chung JM: Effects of sympathectomy on a rat model of peripheral neuropathy. Pain 55:85-92, 1993 Maves TJ, Pechman PS, Gebhart GF, Meller ST: Possible chemical contribution from chromic gut sutures produces
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disorders of pain sensation like those seen in man. Pain 54:57-69, 1993 McLaughlin EM, Janig W, Devor M, Michaelis M: Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 363:543-546, 1993 Michaelis M, Devor M, Janig W: Sympathetic modulation of activity in rat dorsal root ganglion neurons changes over time following peripheral nerve injury. J Neurophysiol 76:753-763, 1996 Mosconi T, Kruger L: Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induce a painful neuropathy: ultrastructural morphometric analysis of axonal alterations. Pain 64:37-57, 1996 Seltzer Z, Dubner R, Shir Y: A novel behavioral model of neuropathic pain disorders produced by partial sciatic nerve injury. Pail) 43:205-218, 1990 Sheen K, Chung JM: Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model. Brain Res 610:62-68, 1993 Tracey DJ, Walker JS: Pain due to nerve damage: are inflammatory mediators involved? Inflamm Res 44: 407-411,1995 Yoon YW, Na HS, Chung JM: Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain 64:27-36, 1996 Zochodne DW, Ho LT: Influence of perivascular peptides on endoneurial blood flow and microvascular resistance in the sciatic nerve of the rat. J Physiol 444:615-630, 1991 Zochodne DW, Ho LT: Hyperemia of injured peripheral nerve: sensitivity to CGRP antagonism. Brain Res 598: 59-66, 1992 Zochodne DW, Ho LT: Evidence that capsaicin hyperemia of rat sciatic vasa nervorum is local, opiate-sensitive and involves mast cells. J Physiol 468:325-333, 1993
An Alternative Mechanism for Neuropathic Pain Nervi Nervorum William D. Willis, Jr.
he Focus article by Doctors Sove and Light calls attention to the generally neglected innervation of nerve sheaths, the nervi nervorum . It is asserted that the hypotheses that were proposed during the last century concerning the diagnosis and treatment of neuropathic and musculoskeletal pain have failed to withstand scientific scrutiny and that the nervi nervorum may be at least one of the "offending agents" that cause neuropathic pain. The Focus article gives a historical review of what is known about the nervi nervorum (including in this category the nervi vasorum nervorum , the nerve fibers that supply the blood vessels within the nerve sheath). They are chiefly unmyelinated axons havinq "free endings" (although some have encapsulated endings) in the layers of connective tissue about peripheral nerves [13], and many of these axons contain neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP) [2,6]. The authors have recently shown that at least some nervi nervorum in the deep paraspinal tissues are nociceptors [7]. The nervi nervorum afferents have multiple, punctate receptive fields and respond to noxious mechanical, chemical , and thermal stimuli. Interestingly, they can also have receptive fields in adjacent muscles or tendons. The authors agree with Asbury and Fields [3] that the nervi nervorum contribute to nerve trunk pain. Damage to a peripheral nerve or application of capsaicin results in hyperemia as a result of the release of SP and CGRP from the nervi nervorum [26,27]. The hyperemia can be prevented by local administration of a
T
From the Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston, TX. Reprint requests: William D. Willis , Jr., MD, Department of Anatomy and Neurosciences, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1069.
Pain Forum 6(3): 193-195, 1997
CGRP antagonist or by depletion of peptides by a previous application of capsaicin [14,27,28]. The authors therefore suggest that the nervi nervorum contribute to inflammation of peripheral nerve. The authors review the structure of the connective tissue layers of peripheral nerves and the effects of mechanical events that cause nerves to be stretched or compressed, as in the carpal tunnel syndrome. Mechanical forces applied to a nerve can activate nociceptors of the nervi nervorum or, if severe, inactivate them. If activated, the nerve fibers can contribute to neurogenic inflammation and pain [24]. A widely used model of neuropathic pain is produced by loose ligation of the sciatic nerves in rats [5]. Several studies point to a role for inflammation in the pain state seen in this model [10,21]. In fact, the pain state can be produced by aligning chromic gut sutures with the sciatic nerve without actually ligating the nerve [18] (however, see also Ref. [21D. Regeneration of damaged nervi nervorum could lead to the formation of a "miniature neuroma-in-continuity" around the nerve. Eventually, scar tissue might form in the epineurium, leading to "chronic friction injury to the nerve," afferent activity if the scar is innervated, and constriction of the nerve. Axonal sprouts grow into damaged nerve [4]; these "secondary" nervi nervorum contribute to the sensitivity of the nerve to mechanical stimuli. They are not branches of the original nervi nervorum , as they have cutaneous receptive fields, unlike the primary nervi nervorum. The formation of adhesions would further complicate the picture. The receptive fields of nervi nervorum in other tissues would help explain the spread of tenderness beyond the site of injury. Although central nervous system changes, such as central sensitization , contribute to chronic pain, maintenance of such changes depends on continual peripheral input from nociceptors. If this input ceases, central
193
194
COMMENTARYlWiliis
sensitization disappears within hours [12,23,25]. The peripheral input has been attributed to ectopic discharges from axonal sprouts in neuromas and from dorsal root ganglion cells [1,15]. Bove and Light hypothesize that a major contributor to this continual peripheral nociceptive input arises from the nervi nervorum.
EVIDENCE IN SUPPORT OFTHE NERVI NERVORUM HYPOTHESIS OF SOVE AND LIGHT Evidence in favor of the hypothesis that inflammation of a nerve involving the nervi nervorum contributes to neuropathic pain is that dexamethasone reduces the inflammation of the nerve and the severity of the pain state in the Bennett and Xie model [10]. Several experiments done by the Galveston group on the Bennett and Xie model of neuropathic pain are also consistent with the hypothesis of Bove and Light. Following loose ligations of the sciatic nerve, a neuroma was found to form on the nerve [8] (see also Ref. [21]). Part of the neuroma was undoubtedly formed by sprouting axons of the nerve trunk; however, part could have been formed as a "neuroma-in-continuity" of the nervi nervorum, as suggested by Bove and Light. When the sciatic nerve was pretreated with lidocaine in the Bennett and Xie model [11], the severity of the pain state was reduced and the pain state was shortened in duration, whereas lidocaine did not alter the pain state produced in the model of neuropathic pain developed by Seltzer et al. [22]. It is difficult to explain this observation based on the duration of action of lidocaine and the assumption that the pain state depends on the initial input from compressed axons. Another interpretation would be that the lidocaine helped minimize peptide release from the nervi nervorum and thus reduced the amount of inflammation of the sciatic nerve in the Bennett and Xie model. The Seltzer et al. model involves tight ligation of the sciatic nerve, which would be associated with a transient injury discharge. Presumably, rather than being maintained by a progressive inflammation of the nerve, the pain state appears to be maintained by ectopic discharges from the dorsal root ganglion. Similarly, in the model of neuropathic pain developed by Kim and Chung [16], one or two spinal nerves are tightly ligated. This would presumably have an effect similar to that of tight ligation of part of the sciatic nerve in the Seltzer et al. model. Ectopic discharges from dorsal root ganglion cells also appear to contribute to the continuous peripheral input that causes central sensitization in the Kim and Chung model; however, in both the Seltzer et al. and Kim and Chung models, inflammation and eventual scarring could also occur, and so it is plausible that discharges would also originate from damaged and regen-
erating nervi nervorum. Maintained peripheral input is known to be required in the model of Kim and Chung to support central sensitization, as the allodynia and hyperalgesia diminish rapidly after the dorsal roots of the ligated segments are sectioned [23,25]; however, dorsal rhizotomy would interfere with discharges originating from the dorsal root ganglion, from a neuroma in the spinal nerve, and from a neuroma involving nervi nervorum.
EVIDENCE THAT IS NOT CONSISTENT WITH THE HYPOTHESIS In many cases of neuropathic pain, including the Kim and Chung model, the pain is sympathetically maintained [17]. The nervi nervorum hypothesis does not address this issue. One explanation for a role of the sympathetic nervous system in maintaining the pain state in the model developed by Kim and Chung is the ingrowth of sympathetic nerve fibers into the dorsal root ganglion in the ligated segments [9]. These sympathetic axons, recognized by their content of tyrosine hydroxylase, form whorls around dorsal root ganglion cells. A similar ingrowth of sympathetic axons also follows a complete transection of the sciatic nerve, although at a much later time [19]. Stimulation of the sympathetic trunk, in such preparations, has been shown to excite dorsal root ganglion cells [20]. There is no reason to implicate the nervi nervorum in this process. Furthermore, most of the pain state in the Kim and Chung model is alleviated by sympathectomy [17J, and so the contribution of the nervi nervorum appears to be minimal in this model of neuropathic pain.
References 1. Amir R, Devor M: Ongoing activity in neuroma afferents bearing retrograde sprouts. Brain Res 630:283-288, 1993 2. Appenzeller 0, Dhital KK, Cowen T, Burnstock G: The nerves to blood vessels supplying nerves: the innervation of vasa nervorum. Brain Res 304:383-386, 1984 3. Asbury AK, Fields HL: Pain due to peripheral nerve damage: an hypothesis. Neurology 34:1587-1590,1984 4. Bennett GJ: An animal model of neuropathic pain: a review. Muscle Nerve 16:1040-1 048, 1993 5. Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87-107,1988 6. Bove GM, Light AR: Calcitonin gene-related peptide and peripherin immunoreactivity in nerve sheaths. Somatosens Mot Res 12:49-57, 1995 7. Bove GM, Light AR: Unmyelinated nociceptors of rat paraspinal tissues. J NeurophysioI73:1752-1762, 1995 8. Carlton SM, Dougherty PM, Pover CM, Coggeshall RE: Neuroma formation and numbers ofaxons in a rat model
COMMENTARY/willis
9.
10.
11.
12.
13.
14.
15.
16.
17.
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of experimental peripheral neuropathy. Neurosci Lett 131:88-92,1991 Chung K, Lee BH, Yoon YW, Chung JM: Sympathetic sprouting in the dorsal root ganglia of the injured peripheral nerve in a rat neuropathic pain model. J Comp Neurol 376:241-252, 1996 Clatworthy AL, lilich PA, Castro GA, Walters ET: Role of peri-axonal inflammation in the development of thermal hyperalgesia and guarding behavior in a rat model of neuropathic pain. Neurosci Lett 184:5-8, 1995 Dougherty PM, Garrison CJ, Carlton SM: Differential influence of local anesthetic upon two models of experimentally induced peripheral mononeuropathy in the rat. Brain Res 570:109-115, 1992 Gracely RH, Lynch SA, Bennett GJ: Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 51:175-194, 1992 Hromada J: On the nerve supply of the connective tissue of some peripheral nervous tissue system components. Acta Anat 55:343-351, 1963 Jansco N, Jansco-Gabor A, Szolcsanyi J: Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol Chemother31:138-151, 1967 Kajander KC, Wakisaka S, Bennett GJ: Spontaneous discharge originates in the dorsal root ganglion at the onset of a painful peripheral neuropathy in the rat. Neurosci Lett 138:225-228, 1992 Kim SH, Chung JM: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355-363, 1992 Kim SH, Na HS, Sheen K, Chung JM: Effects of sympathectomy on a rat model of peripheral neuropathy. Pain 55:85-92, 1993 Maves TJ, Pechman PS, Gebhart GF, Meller ST: Possible chemical contribution from chromic gut sutures produces
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
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disorders of pain sensation like those seen in man. Pain 54:57-69, 1993 McLaughlin EM, Janig W, Devor M, Michaelis M: Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 363:543-546, 1993 Michaelis M, Devor M, Janig W: Sympathetic modulation of activity in rat dorsal root ganglion neurons changes over time following peripheral nerve injury. J Neurophysiol 76:753-763, 1996 Mosconi T, Kruger L: Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induce a painful neuropathy: ultrastructural morphometric analysis of axonal alterations. Pain 64:37-57, 1996 Seltzer Z, Dubner R, Shir Y: A novel behavioral model of neuropathic pain disorders produced by partial sciatic nerve injury. Pail) 43:205-218, 1990 Sheen K, Chung JM: Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model. Brain Res 610:62-68, 1993 Tracey DJ, Walker JS: Pain due to nerve damage: are inflammatory mediators involved? Inflamm Res 44: 407-411,1995 Yoon YW, Na HS, Chung JM: Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain 64:27-36, 1996 Zochodne DW, Ho LT: Influence of perivascular peptides on endoneurial blood flow and microvascular resistance in the sciatic nerve of the rat. J Physiol 444:615-630, 1991 Zochodne DW, Ho LT: Hyperemia of injured peripheral nerve: sensitivity to CGRP antagonism. Brain Res 598: 59-66, 1992 Zochodne DW, Ho LT: Evidence that capsaicin hyperemia of rat sciatic vasa nervorum is local, opiate-sensitive and involves mast cells. J Physiol 468:325-333, 1993