Search

The mechanistic interactions among redox status of leukocytes, muscle, and exercise in pain regulation are still poorly understood and limit targeted treatment. Exercise benefits are numerous, including the treatment of chronic pain. However, unaccustomed exercise may be reported as undesirable as it may contribute to pain. The aim of the present review is to evaluate the relationship between oxidative metabolism and acute exercise-induced pain, and as to whether improved antioxidant capacity underpins the analgesic effects of regular exercise. Preclinical and clinical studies addressing relevant topics on mechanisms by which exercise modulates the nociceptive activity and how redox status can outline pain and analgesia are discussed, in sense of translating into refined outcomes. Emerging evidence points to the role of oxidative stress-induced signaling in sensitizing nociceptor sensory neurons. In response to acute exercise, there is an increase in oxidative metabolism, and consequently, pain. Instead, regular exercise can modulate redox status in favor of antioxidant capacity and repair mechanisms, which have consequently increased resistance to oxidative stress, damage, and pain. Data indicate that acute sessions of unaccustomed prolonged and/or intense exercise increase oxidative metabolism and regulate exercise-induced pain in the post-exercise recovery period. Further, evidence demonstrates regular exercise improves antioxidant status, indicating its therapeutic utility for chronic pain disorders. An improved comprehension of the role of redox status in exercise can provide helpful insights into immune-muscle communication during pain modulatory effects of exercise and support new therapeutic efforts and rationale for the promotion of exercise.

The voltage-gated sodium channel Na(V)1.9 is preferentially expressed in nociceptors and has been shown in rodent models to have a major role in inflammatory and neuropathic pain. These studies suggest that by selectively targeting Na(V)1.9, it might be possible to ameliorate pain without inducing adverse CNS side effects such as sedation, confusion and addictive potential. Three recent studies in humans--two genetic and functional studies in rare genetic disorders, and a third study showing a role for Na(V)1.9 in painful peripheral neuropathy--have demonstrated that Na(V)1.9 plays an important part both in regulating sensory neuron excitability and in pain signalling. With this human validation, attention is turning to this channel as a potential therapeutic target for pain.

Background: Itch is one of the major somatosensory modalities. Some recent findings have proposed that gastrin releasing peptide (Grp) is expressed in a subset of dorsal root ganglion (DRG) neurons and functions as a selective neurotransmitter for transferring itch information to spinal cord interneurons. However, expression data from public databases and earlier literatures indicate that Grp mRNA is only detected in dorsal spinal cord (dSC) whereas its family member neuromedin B (Nmb) is highly expressed in DRG neurons. These contradictory results argue that a thorough characterization of the expression of Grp and Nmb is warranted., Findings: Grp mRNA is highly expressed in dSC but is barely detectable in DRGs of juvenile and adult mice. Anti-bombesin serum specifically recognizes Grp but not Nmb. Grp is present in a small number of small-diameter DRG neurons and in abundance in layers I and II of the spinal cord. The reduction of dSC Grp after dorsal root rhizotomy is significantly different from those of DRG derived markers but similar to that of a spinal cord neuronal marker. Double fluorescent in situ of Nmb and other molecular markers indicate that Nmb is highly and selectively expressed in nociceptive and itch-sensitive DRG neurons., Conclusion: The majority of dSC Grp is synthesized locally in dorsal spinal cord neurons. On the other hand, Nmb is highly expressed in pain- and itch-sensing DRG neurons. Our findings provide direct anatomic evidence that Grp could function locally in the dorsal spinal cord in addition to its roles in DRG neurons and that Nmb has potential roles in nociceptive and itch-sensitive neurons. These results will improve our understanding about roles of Grp and Nmb in mediating itch sensation.

The available data on the innervation of the thoracolumbar fascia (TLF) are inconsistent and partly contradictory. Therefore, the role of the fascia as a potential source of pain in the low back is difficult to assess. In the present study, a quantitative evaluation of calcitonin gene-related peptide (CGRP) and substance P (SP)-containing free nerve endings was performed in the rat TLF. A preliminary non-quantitative evaluation was also performed in specimens of the human TLF. The data show that the TLF is a densely innervated tissue with marked differences in the distribution of the nerve endings over the fascial layers. In the rat, we distinguished three layers: (1) Outer layer (transversely oriented collagen fibers adjacent to the subcutaneous tissue), (2) middle layer (massive collagen fiber bundles oriented obliquely to the animal's long axis), and (3) inner layer (loose connective tissue covering the paraspinal muscles). The subcutaneous tissue and the outer layer showed a particularly dense innervation with sensory fibers. SP-positive free nerve endings-which are assumed to be nociceptive-were exclusively found in these layers. Because of its dense sensory innervation, including presumably nociceptive fibers, the TLF may play an important role in low back pain., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

In anaesthetised rats, systematic electrophysiological recordings from dorsal horn neurones in spinal segments Th13-L5 were made to obtain information about the spinal nociceptive processing from the lumbar thoracolumbar fascia. Six to fourteen percent of the neurones in the spinal segments Th13-L2 had nociceptive input from the thoracolumbar fascia in naïve animals, no neurones responsive to input from the lumbar fascia were found in segments L3-L5. The segmental location of the receptive fields in the fascia was shifted 2-4 segments caudally relative to the spinal segment recorded from. Most neurones were convergent in that they received additional input from other deep somatic tissues in the low back (87%) and from the skin in the abdominal wall or the proximal leg (50%). The proportion of neurones responsive to input from the thoracolumbar fascia rose significantly from 4% to 15% (P<0.05) in animals with an experimentally-induced inflammation of a low back muscle (multifidus). Moreover, neurones in spinal segment L3 - that did not receive input from the fascia in normal animals - responded to fascia input in animals with inflamed muscle. The data suggest that the nociceptive input from the thoracolumbar fascia contributes to the pain in low back pain patients., (Copyright © 2011 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Background: Sprouting of sympathetic fibers into sensory ganglia occurs in many preclinical pain models, providing a possible anatomical substrate for sympathetically enhanced pain. However, the functional consequences of this sprouting have been controversial. We used a transgenic mouse in which sympathetic fibers expressed green fluorescent protein, observable in live tissue. Medium and large diameter lumbar sensory neurons with and without nearby sympathetic fibers were recorded in whole ganglion preparations using microelectrodes., Results: After spinal nerve ligation, sympathetic sprouting was extensive by 3 days. Abnormal spontaneous activity increased to 15% and rheobase was reduced. Spontaneously active cells had Aαβ conduction velocities but were clustered near the medium/large cell boundary. Neurons with sympathetic basket formations had a dramatically higher incidence of spontaneous activity (71%) and had lower rheobase than cells with no sympathetic fibers nearby. Cells with lower density nearby fibers had intermediate phenotypes. Immunohistochemistry of sectioned ganglia showed that cells surrounded by sympathetic fibers were enriched in nociceptive markers TrkA, substance P, or CGRP. Spontaneous activity began before sympathetic sprouting was observed, but blocking sympathetic sprouting on day 3 by cutting the dorsal ramus in addition to the ventral ramus of the spinal nerve greatly reduced abnormal spontaneous activity., Conclusions: The data suggest that early sympathetic sprouting into the sensory ganglia may have highly localized, excitatory effects. Quantitatively, neurons with sympathetic basket formations may account for more than half of the observed spontaneous activity, despite being relatively rare. Spontaneous activity in sensory neurons and sympathetic sprouting may be mutually re-enforcing.

Background: The transient receptor potential (TRP) channel subtype A1 (TRPA1) is known to be expressed on sensory neurons and respond to changes in temperature, pH and local application of certain noxious chemicals such as allyl isothiocyanate (AITC). Artemin is a neuronal survival and differentiation factor and belongs to the glial cell line-derived neurotrophic factor (GDNF) family. Both TRPA1 and artemin have been reported to be involved in pathological pain initiation and maintenance. In the present study, using whole-cell patch clamp recording technique, in situ hybridization and behavioral analyses, we examined the functional interaction between TRPA1 and artemin., Results: We found that 85.8 ± 1.9% of TRPA1-expressing neurons also expressed GDNF family receptor alpha 3 (GFR α3), and 87.5 ± 4.1% of GFRα3-expressing neurons were TRPA1-positive. In whole-cell patch clamp analysis, a short-term treatment of 100 ng/ml artemin significantly suppressed the AITC-induced TRPA1 currents. A concentration-response curve of AITC resulting from the effect of artemin showed that this inhibition did not change EC50 but did lower the AITC-induced maximum response. In addition, pre-treatment of artemin significantly suppressed the number of paw lifts induced by intraplantar injection of AITC, as well as the formalin-induced pain behaviors., Conclusions: These findings that a short-term application of artemin inhibits the TRPA1 channel's activity and the sequential pain behaviors suggest a role of artemin in regulation of sensory neurons.

The purpose of this study was to determine whether α(1)-adrenoceptors are expressed on primary nociceptive afferents that innervate healthy skin. Skin and dorsal root ganglia were collected from adult male Wistar rats and assessed using fluorescence immunohistochemistry with antibodies directed against α(1)-adrenoceptors alone or in combination with specific labels including myelin basic protein and neurofilament 200 (markers of myelinated nerve fibres), protein gene product 9.5 (a pan-neuronal marker), tyrosine hydroxylase (sympathetic neurons), isolectin B(4) (IB(4): non-peptidergic sensory neurons), calcitonin gene related peptide (CGRP) and transient receptor potential vanilloid receptor 1 (TRPV1) (peptidergic sensory neurons). Double labelling in dorsal root ganglia confirmed the expression of α(1)-adrenoceptors within sub-populations of CGRP, IB(4) and TRPV1 immunoreactive neurons. Myelinated and unmyelinated sensory nerve fibres in the skin expressed α(1)-adrenoceptors whereas sympathetic nerve fibres did not. The expression of α(1)-adrenoceptors on C- and A-delta nociceptive afferent fibres provides a histochemical substrate for direct excitation of these fibres by adrenergic agonists. This may help to explain the mechanism of sensory-sympathetic coupling that sometimes develops on surviving primary nociceptive afferents in neuropathic pain states., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

This study analyzed the relationship between the density of intraepidermal nerve fibers (IENF) and the characteristics of either nociceptive laser-evoked potentials (LEPs) or contact heat-evoked potentials (CHEPs) in patients with painful sensory polyneuropathy with the aim to determine which parameters of LEPs and CHEPs more reliably reflect IENF loss. A total of 96 patients and 35 healthy volunteers took part in the study. Based on clinical examination, nerve conduction tests, and quantitative sensory testing, we identified 52 patients with small-fiber neuropathy (SFN), 40 with mixed (small-fiber and large-fiber) neuropathy (MFN), and 4 who were excluded from the analysis because of no evidence of involvement of small fibers. The latency of the N2 was delayed for both LEPs and CHEPs in patients with MFN and for CHEPs only in patients with SFN. The amplitude of the vertex N2/P2 potential was similarly reduced in both types of neuropathy, but LEPs were more frequently absent than CHEPs in MFN patients (68% vs 40%). In general, latency and amplitude of LEPs and CHEPs were well correlated with IENF density. SFN patients were characterized by abnormal EPs and slightly decreased but morphologically abnormal IENF. MFN patients were characterized by frequently absent LEPs and CHEPs and a rather severe IENF loss. The correlation between nociceptive evoked potentials (laser-evoked potentials and contact heat-evoked potentials) and skin biopsy aids in the diagnosis of painful neuropathies., (Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Calcitonin gene-related peptide (CGRP) is linked to neurogenic inflammation and to migraine. Activation of the trigeminovascular system plays a prominent role during migraine attacks with the release of CGRP. The trigeminal ganglion (TG) contains three main cell types: neurons, satellite glial cells (SGC) and Schwann cells; the first two have before been studied in vitro separately. Culture of rat TG provides a method to induce inflammation and the possibility to evaluate the different cell types in the TG simultaneously. We investigated expression levels of various inflammatory cytokines on mRNA level using RT-PCR arrays and qRT-PCR; furthermore expression at protein level was studied using immunohistochemistry. We report that (1) organ culture of the TG is possible with preserved morphology, (2) organ culture is associated with enhanced expression of cytokines and mitogen-activated protein kinases (MAPKs) primarily in neurons, (3) CGRP can induce expression of some cytokines and (4) cytokine expression is still upregulated following MAPK pathway inhibition by MEK inhibitor U0126 and pp38 inhibitor SB202192, but the cytokine expression is abolished when co-incubating with the JNK inhibitor SP600125. This method may be of value to examine local TG inflammation, putatively involved in the pathophysiology of some forms of primary headaches.

The cannabinoid receptor CB1 is involved in modulation of neuronal hypersensitivity and pain. The aim of this study was to evaluate CB1 receptor levels for the first time in dental pain. A total of 19 patients due for molar extraction were divided into two groups, those with existing dental pain (n=9), and those with no history of pain (n=10). Immunohistochemistry and computer image analysis was used to evaluate CB1-positive nerve fibres in tooth pulp, with neurofilament-immunostaining as a structural nerve marker. CB1-immunoreactive nerve fibres were scattered throughout the tooth pulp and often seen in nerve bundles, but the fibres did not penetrate the subodontoblastic layer. There was no statistically significant change in the CB1 nerve fibre percentage area in the painful group compared to the non-painful group (p=0.146); the neurofilament fibres were significantly reduced in the painful group compared to the controls (p=0.028), but there was no difference in the ratio of CB1 to neurofilaments between the two groups. Thus, CB1 expression is maintained by nerve fibres in painful human dental pulp, and peripherally-restricted CB1 agonists currently in development may advance the treatment of dental pain., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Study Design: Investigation of sensory innervation of rat osteoporotic lumbar vertebrae using in vitro and in vivo models., Objective: To investigate (1) sensory innervation of osteoporotic rat vertebrae, (2) effects of risedronate on sensory neurons, (3) effects of osteoporosis treatment on bone mineral densities (BMDs) and the sensory innervation., Summary of Background Data: Osteoporotic patients without fractures sometimes experience vague low back pain of unknown origin. The mechanisms of osteoporosis treatments against the pain are unclear., Methods: (1) The expression of calcitonin gene-related peptide (CGRP) immunoreactive (-ir) or transient receptor potential vanilloid 1 (TRPV1)-ir nerve fibers in vertebrae and dorsal root ganglions (DRG) innervating L3 vertebrae of Sprague Dawley rats labeled with neurotracer were examined in control, sham, and ovariectomized (OVX) rats. (2) Cultured rat neonate DRG neurons in media containing different concentrations of risedronate were immunostained for CGRP, and we measured its activity using axonal length and proportion of CGRP-ir neurons. (3) BMDs and CGRP expression in DRG neurons innervating L3 vertebrae were examined in the following 5 groups: sham (treated with saline), OVX (saline), OVX+EXE (treadmill exercise), OVX+RIS (risedronate), and OVX+RIS+EXE (risedronate and exercise)., Results: (1) A few CGRP-ir or TRPV1-ir nerve fibers were observed in the bone marrow. CGRP or TRPV1 expression in DRG was elevated in the OVX group (P < 0.05). (2) The axonal length and proportion of CGRP-ir neurons were dose-dependently suppressed (P < 0.05). (3) BMDs improved and the CGRP expression decreased in the risedronate-treated groups (P < 0.05), especially in the OVX+RIS+EXE group., Conclusion: Sensory innervation of osteoporotic rat vertebrae showed increased expression of CGRP and TRPV1 in DRG neurons. Risedronate suppressed activity of CGRP-ir neurons in vitro, improved BMD, and decreased CGRP expression, especially together with exercise in vivo.

Background: Pain is a major debilitating factor in osteoarthritis (OA), yet few mechanism-based therapies are available. To address the need to understand underlying mechanisms the aim of the present study was to determine changes in sensory neurons in an animal model of OA pain., Results: The model displayed typical osteoarthritis pathology characterized by cartilage degeneration in the knee joint and also manifested knee pathophysiology (edema and increased vasculature permeability of the joint) and altered nociception of the affected limb (hind paw tenderness and knee articulation-evoked reduction in the tail flick latency). Neurons included in this report innervated regions throughout the entire hind limb. Abeta-fiber low threshold mechanoreceptors exhibited a slowing of the dynamics of action potential (AP) genesis, including wider AP duration and slower maximum rising rate, and muscle spindle neurons were the most affected subgroup. Only minor AP configuration changes were observed in either C- or Adelta-fiber nociceptors., Conclusion: Thus, at one month after induction of the OA model Abeta-fiber low threshold mechanoreceptors but not C- or Adelta-fiber nociceptors had undergone changes in electrophysiological properties. If these changes reflect a change in functional role of these neurons in primary afferent sensory processing, then Abeta-fiber non-nociceptive primary sensory neurons may be involved in the pathogenesis of OA pain. Further, it is important to point out that the patterns of the changes we observed are consistent with observations in models of peripheral neuropathy but not models of peripheral inflammation.

The primary aim of our study was to demonstrate how the diagnostic characteristics of skin biopsy used to evaluate small fiber involvement in patients with different causes of polyneuropathy are intrinsically related to the method used to establish the reference values (cut-off values). We also investigated intraepidermal nerve fiber (IENF) density and abnormalities in quantitative sensory testing (QST) in patients with different causes of polyneuropathy and signs of small fiber involvement. A total of 210 patients with symptoms and signs of polyneuropathy were entered into the study. All patients underwent neurological examination, nerve conduction studies, QST on the thigh and distal part of the calf with detection of warm and cold perception thresholds, and skin biopsy with assessment of IENF density. Cut-off values for IENF density were established from our reference material using Z-scores (calculated from multiple regression analysis), fifth percentile, and receiver operating characteristic (ROC) analysis. Of the patients participating in the study, 65 had an established diagnosis of diabetes mellitus, 70 were classified with idiopathic polyneuropathy, and 75 had other possible causes of polyneuropathy. Forty-five patients met the criteria for small fiber polyneuropathy (SFN), and the remaining 165 had also involvement of large nerve fibers. Of the total patient cohort, 84 (40%) had reduced IENF density based on the Z-score, and 106 patients (50%) had at least one abnormality based on QST. In the SFN group, skin biopsy showed a sensitivity of 31% and a specificity of 98% when reference values were presented with Z-scores. When the fifth percentile was used as the cut-off value (6.7 fibers/mm), sensitivity was 35% and specificity 95%. Applying the ROC analysis with a chosen sensitivity of 78% and specificity of 64%, we had a cut-off point of 10.3 fibers/mm. We conclude that skin biopsy with assessment of IENF is a useful method for investigating patients with SFN. The diagnostic value of the test, however, depends upon on the approach used to estimate the reference values.

Since the dorsal root ganglia represent the first structure of pain modulation, they are the target of the newest therapies of neuropathic pain. Between these, pulsed radiofrequency (PRF) has been described among the promising non-invasive methods. Although the results encourage the clinical use of this procedure, their mechanism of action is still unclear. Aim of our study was to analyze acute effects of PRF on the rat lumbar ganglion and on nervous fibres running inside it. Clinical works describe PRF treatment as a technique without any visible neurological deficit. The few disposable histological works are contractictory: some describe no signs of cellular damage and some demonstrate visible intracellular modifications. A total of 20 male Wistar rats were deeply anesthesized. Ten were positioned in a stereotactic system, and exposed to PRF at 2 Hz for 30 s after exposition of paravertebral muscles and positioning of a stimulation needle on left L4 ganglion. The other ten were used as controls. After 1 h, the left dorsal root ganglions L3, L4, L5 of the 20 animals were explanted, fixed in 2.5% Karnowsky solution and prepared for light and transmission electron microscopy. At light microscopy no differences between treated and control animals were observed; at transmission electron microscopy, instead, it was possible to observe that T gangliar cells contained an abnormal abundant smooth reticulum with enlarged cisternae and numerous vacuoles; myelinated axons presented pathological features and their myelin coverage was not adherent. Instead, unmyelinated axons appeared normal in shape and dimension and the Schwann cells surrounding it had intact plasmamembrane. Our results, obtained at acute stage, reveal that the PRF procedure should destroy the myelin envelope of nervous fibres. Further future studies, at chronic stage, should give other information on the prognosis of the myelinic damage.

Painful diabetic neuropathy causes hyperalgesia and does not respond to commonly used analgesics such as non-steroidal anti-inflammatory drugs or opioids at doses below those producing disruptive side effects. In the present study, we examined the effect of P2X receptor antagonists, which are known to modulate the pain pathway, on mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic mice. The paw withdrawal frequency measured by von Frey filaments, began to significantly increase 5 days after STZ injection and was maintained for more than 14 days. Intrathecal administration of P2X receptor antagonists (PPADS and TNP-ATP) inhibited the mechanical allodynia in diabetic mice. The levels of P2X(2) and P2X(3) receptors mRNA were significantly increased in diabetic mice at 14 days after the intravenous injection of STZ. These results suggest that the upregulation of P2X(2), P2X(3) and/or P2X(2/3) receptor in DRG neurons is associated with mechanical allodynia in STZ-induced diabetic mice.

The role of Glutamate (Glu), one of the major excitatory neurotransmitters in the central nervous system, has been thoroughly investigated in animal models and in humans in several physiologic events, such as brain development and synaptic plasticity, but also in acute and chronic neurologic diseases and psychiatric disorders. Recently, it has been demonstrated that Glu is important for sensory input transduction, particularly along the nociceptive pathway. Glu involvement in peripheral neuropathies has also been suggested on the basis of experimental studies in animals, thus widening the spectrum of possible sites of action of this neurotransmitter from the central to the peripheral nervous system. This rather unexpected observation may have important therapeutic implications, provided that a complete characterization of the glutamatergic system in the peripheral nervous system is achieved and its changes under the different pathological conditions are investigated. This review will focus on the most recent advances in the research into the role of Glu and the glutamatergic system in the pathology of the peripheral nervous system.

In this prospective study, intraepidermal nerve fiber densities (IENFD) and subepidermal nerve plexus densities (SENPD) were quantified by immunostaining in skin punch biopsies from the distal calf in 99 patients with clinical symptoms of painful sensory neuropathy and from 37 age-matched healthy volunteers. The clinical diagnosis was based on history and abnormal thermal thresholds on quantitative sensory testing (QST). In patients with neuropathy, IENFD and SENPD were reduced to about 50% of controls. Elevated warm detection thresholds on QST correlated with IENFD but not with SENPD. Using receiver-operating characteristic (ROC) curve analysis of IENFD values, the diagnostic sensitivity for detecting neuropathy was 0.80 and the specificity 0.82. For SENPD, sensitivity was 0.81 and specificity 0.88. With ROC analysis of both IENFD and SENPD together, the diagnostic sensitivity was further improved to 0.92. The combined examination of IENFD and SENPD is a highly sensitive and specific diagnostic tool in patients suspected to suffer from painful sensory neuropathies but with normal values on clinical neurophysiological studies.

Quantitation of epidermal nerve fiber (ENF) density is an objective diagnostic test of small fiber neuropathy (SFN). For a diagnostic test to be clinically useful it should correspond well with clinically meaningful physical findings. We performed a retrospective analysis of the concordance between foot ENF density and clinical findings in all patients seen at our institution with possible idiopathic SFN who underwent skin biopsy for ENF density determination. We found a high concordance between reduced foot ENF density and loss of pinprick sensitivity in this patient population. Our findings indicate that ENF density determination is a clinically relevant objective test in patients undergoing evaluation for possible SFN.

Chronic constriction injury (CCI) and partial ligation (PSNL) of the sciatic nerve induce a similar neuropathic pain syndrome in rats. We examined calcitonin gene-related peptide (CGRP), substance P (SP) and protein gene product (PGP) 9.5 immunoreactive (IR) axons in the footpad skin after the two types of injury. Four and 14 days after CCI, CGRP- and SP-IR axons in the ipsilateral footpad skin disappeared in most rats, but in one third, sparse CGRP- and SP-IR fibers remained. PGP-IR axons dramatically decreased, but some thick fiber fascicles appeared. At the ultrastructural level, these PGP-IR thick fiber fascicles were characterized as unmyelinated axons surrounded by non-IR Schwann cells. Some of these axons were swollen and irregular in shape. In contrast, 4 days after PSNL, CGRP-, SP-, and PGP-IR axons in the ipsilateral footpad skin were present, though significantly reduced in density, in all rats, and by 14 days all IR fiber densities in the footpad skin partially recovered. The loss of CGRP and SP axons in the footpad skin of the CCI model suggests that sensory nerves containing neuropeptides are not essential in transducing stimuli applied to the footpad skin into neuropathic pain, but the abnormal PGP-IR unmyelinated axons in thick fiber fascicles might play a role. The partial loss and rapid recovery of IR axons in the footpad skin after PSNL shows that the two injury models, causing similar behaviors, are associated with very different patterns of cutaneous innervation at the time when the pain syndrome is well developed.