Partial sciatic nerve ligation induced more dramatic increase of neuropeptide Y immunoreactive axonal fibers in the gracile nucleus of middle-aged rats than in young adult rats.

Neuropeptide changes in primary sensory neurons caused by partial nerve injury are likely involved in the development of neuropathic pain. In this study, using immunocytochemistry, we examined neuropeptide Y (NPY) expression in lumbar dorsal root ganglion (DRG) cells of young adult (2-3 months old) and middle-aged (8-10 months old) rats 4 weeks after partial sciatic nerve ligation (PSNL). Significantly higher NPY immunoreactivity was induced in the injured side DRG neurons, the dorsal horn and the gracile nuclei in middle-aged rats than in young rats. Using combined fluorescent dye tracing and NPY immunostaining, we found in middle-aged rats that 46% injured DRG neurons projected to the gracile nucleus and 45% of injured neurons were also NPY-IR, whereas 42% spared DRG neurons projected to the gracile nucleus and 18% of spared neurons were also NPY-IR. Thus PSNL induces NPY up-regulation in spared as well as injured DRG neurons, both contribute to the increased NPY immunoreactivity in the gracile nucleus in the middle-aged rats. The more dramatic increase of NPY in DRG neurons of middle-aged rats after PSNL shows that the responses to partial nerve injury are age-dependent, that suggests a possible relevance to the higher incidence of neuropathic pain in human middle age.

Calcitonin gene-related peptide, substance P and protein gene product 9.5 immunoreactive axonal fibers in the rat footpad skin following partial sciatic nerve injuries.

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.

Partial sciatic nerve transection induced tyrosine hydroxidase immunoreactive axon sprouting around both injured and spared dorsal root ganglion neurons which project to the gracile nucleus in middle-aged rats.

After partial sciatic nerve transection (PSNT), sympathetic axons sprout into the lumbar dorsal root ganglia (DRG), a phenomenon implicated in neuropathic pain. We asked whether sympathetic sprouting is directed to injured or spared DRG neurons and whether these neurons project to the gracile nucleus. Using combined fluorescent dye tracing and tyrosine hydroxylase (TH) immunohistochemistry, we found that 4 weeks after PSNT in rats 8-10 months old, 51% of the neurons surrounded by TH-immunoreactive (IR) axons were spared, while 43% were injured. Seventy-nine percent projected to the gracile nucleus. Sympathetic sprouting induced by PSNT is not directed preferentially to injured or spared DRG neurons, but does show a preference for DRG neurons projecting to the gracile nucleus.

Improved survival of injured sciatic nerve Schwann cells in mice lacking the p75 receptor.

Following nerve injury, there is a dramatic increase in the expression of the p75 neurotrophin receptor on Schwann cells (Heumann, R., Korsching, S., Bandtlow, C. and Thoenen, H., Changes of nerve growth factor synthesis in non-neuronal cells in response to sciatic nerve transection. J. Cell Biol., 104 (1987) 1623-1631. Taniuchi, M., Clark, H.B., Schweitzer, J.B. and Johnson, E.M., Expression of nerve growth factor by Schwann cells of axotomized peripheral nerves: ultrastructural location, suppression by axonal contact, and binding properties. J. Neurosci., 8 (1988) 664-681.), however the role of the p75 receptor following injury remains unclear. Previous studies have shown that the p75 receptor may play a role in the apoptosis of several cell types. To better understand the role of the p75 receptor in the events following nerve injury, we have compared apoptosis in injured sciatic nerves of adult mice lacking functional p75 receptors and Balb-C (wild-type) mice. Following sciatic nerve crush or resection injuries, we used a fluorescent FragEL DNA fragmentation method to examine the extent of cellular apoptosis in distal nerve segments 5 days, 21 days and 4 months later. Nerve injury induced large numbers of apoptotic nuclei in nerves of both strains, but in p75 knockout mice, the density of apoptotic cells was lower compared to Balb-C mice, 21 days following injury. The p75 receptor may promote apoptosis in Schwann cells when axons are regenerating into the denervated nerve stump.

Increased calcitonin gene-related peptide immunoreactivity in gracile nucleus after partial sciatic nerve injury: age-dependent and originating from spared sensory neurons.

Following a unilateral chronic constriction injury of the sciatic nerve, calcitonin gene-related peptide (CGRP)-immunoreactive (IR) fiber density increases in the ipsilateral gracile nucleus, and this is more pronounced in aged (16-month) rats where the fibers are dystrophic. In this study we show that a second type of partial sciatic nerve injury, a half-transection, also induces CGRP-IR fibers in the gracile nucleus, but this effect is strongly age-dependent, being much more pronounced in 8- to 10-month-old rats than in 2- to 3-month-old rats. Dystrophic CGRP-IR fibers were rarely observed in 8- to 10-month-old animals, so the increased reaction in aged animals and axonal dystrophy are separate phenomena. Using double-labeling with fluorescent dye tracing for 8- to 10-month-old rats, we showed that neuron profiles in the dorsal root ganglion (DRG) with peripheral axons spared by the partial sciatic nerve injury were 10 times more likely to be CGRP mRNA-positive than profiles with injured peripheral axons, suggesting that spared neurons are more likely to contribute to the increase in CGRP-IR fibers in the gracile nucleus. Using combined fluorescent dye tracing with in situ hybridization for CGRP mRNA or CGRP immunostaining, we further showed that CGRP-expressing DRG neuron profiles with central projections to the gracile nucleus had peripheral axons spared by the partial nerve injury. We conclude that the increased CGRP immunoreactivity in the gracile nucleus following partial sciatic nerve injury originates from primary sensory neurons with axons spared by the injury. These neurons may still transmit cutaneous sensory information and thus the increased CGRP immunoreactive fibers in the gracile nucleus may be involved in the mechanical allodynia characteristic of neuropathic pain syndromes following partial nerve injury.

Ultrastructural localization of increased neuropeptide immunoreactivity in the axons and cells of the gracile nucleus following chronic constriction injury of the sciatic nerve.

Neuropeptide plasticity in the gracile nucleus is thought to play a role in the development of neuropathic pain following nerve injury. Two weeks after chronic constriction injury of adult rat sciatic nerve, galanin, neuropeptide Y and calcitonin gene-related peptide immunoreactivities were increased in fibers and cells in the gracile nucleus ipsilateral to injury. At the electron microscopic level, this increased neuropeptide immunoreactivity was localized in myelinated axons, boutons, dendrites, neurons and glial cells. Galanin-, neuropeptide Y- and calcitonin gene-related peptide-immunoreactive boutons were frequently presynaptic to dendrites of both immunoreactive and non-immunoreactive neurons. However, no neuropeptide Y, galanin and calcitonin gene-related peptide messenger RNA was detected in the injured side gracile nuclei by in situ hybridization. These results show that partial nerve injury to the sciatic nerve induces increases in the content of galanin, neuropeptide Y and calcitonin gene-related peptide immunoreactivities in synaptic terminals within the gracile nucleus, which suggests that there may be increased release of these neuropeptides following sensory or spontaneous stimulation of large-diameter primary afferents following partial nerve injury, perhaps one mechanism involved in neuropathic pain. We also show an apparent transfer of these neuropeptides to the cells of the gracile nucleus, both neurons and glial cells, an intriguing phenomenon of unknown functional significance.

Endogenous interleukin-6 contributes to hypersensitivity to cutaneous stimuli and changes in neuropeptides associated with chronic nerve constriction in mice.

Partial nerve injury is a potential cause of distressing chronic pain for which conventional analgesic treatment with opiates or anti-inflammatory agents is not very effective. Constriction nerve injury, widely used to study neuropathic pain, was shown here to induce interleukin-6 (IL-6) mRNA in a subset of rat primary sensory neurons. When we inflicted chronic nerve constriction on mice with null mutation of the IL-6 gene, the hypersensitivity to cutaneous heat and pressure that is induced in wild-type mice was not evident, the loss of substance P in sensory neurons was excessive and the induction of galanin in central sensory projections was reduced. In additional experiments, intrathecal infusion of IL-6 in rats was shown to stimulate synthesis of galanin in approximately one-third of lumbar dorsal root ganglion neurons. The results of these experiments indicate that endogenous IL-6 mediates some of the hypersensitive responses that characterize peripheral neuropathic pain, and influences two neuropeptides that have been implicated in pain transmission.

Increase of galanin mRNA in lumbar dorsal root ganglion neurons of adult rats after partial sciatic nerve ligation.

Partial sciatic nerve ligation (PSNL) is a widely used model for the study of neuropathic pain. However, there is little information on neuropeptide expression in primary sensory neurons after PSNL. We examined galanin (GAL) mRNA expression in L4 and L5 dorsal root ganglion (DRG) neurons of adult rats after PSNL. We found that 4 and 14 days after PSNL the percentages of GAL mRNA positive neurons were significantly increased in the ipsilateral DRG compared to the contralateral side. Using combined retrograde fluorescent dye tracing and in situ hybridization, we found that 47% of the injured neurons and 10% of the spared neurons were GAL mRNA positive. Since only 2-3% of neurons in the contralateral uninjured DRG were GAL mRNA positive, PSNL induced up-regulation of GAL mRNA in both injured and spared DRG neurons.

Adrenergic innervation of rat sensory ganglia following proximal or distal painful sciatic neuropathy: distinct mechanisms revealed by anti-NGF treatment.

Sympathetic axons invade dorsal root ganglia (DRG) following nerve injury, and activity in the resulting pericellular axonal 'baskets' may underlie painful sympathetic-sensory coupling. Sympathetic sprouting into the DRG may be stimulated by nerve growth factor (NGF). To test this hypothesis, we investigated the effect of daily anti-NGF administration on pain and on sprouting in the DRG induced by chronic sciatic constriction injury (CCI) or L5 spinal nerve ligation (SNL). These models have been shown to differ subtly in the onset of pain behaviours and adrenergic sprouting, and we now demonstrate a fundamental difference in the way sympathetic axons invade the DRG: after CCI, perivascular noradrenergic collaterals sprouted into the DRG in a manner dependent upon peripherally derived NGF. In contrast, after SNL, regenerating sympathetic axons were diverted towards the DRG from the spinal nerve by the obstructing ligature, and this effect was only moderately impeded by anti-NGF. The differential dependence on anti-NGF suggests that adrenergic innervation of the DRG after SNL and CCI may reflect regenerative and collateral sprouting, respectively. Pain behaviour was similarly affected: anti-NGF completely prevented CCI-induced thermal hyperalgesia and mechanoallodynia, but the same treatment only partly relieved these symptoms following SNL. These differences emphasize that although CCI and SNL may result in similar behavioural abnormalities, the underlying mechanisms may be governed by distinct processes, differentially dependent on peripheral NGF. These mechanistic differences will have to be considered in the development of appropriate treatment strategies for neuropathic pain produced by different types of pathology.

Sympathetic axons surround neuropeptide-negative axotomized sensory neurons.

Nerve injury can lead to sympathetically dependent neuropathic pain. A possible site of sympathetic-sensory interaction is the dorsal root ganglion (DRG), where sympathetic axons form pericellular 'baskets' around a subpopulation of DRG neurons. Since these structures possibly represent functional units of sympathetic pain, we attempted to characterize the neuropeptidergic phenotype of basketed DRG neurons. We performed double-labeling immunohistochemistry for tyrosine hydroxylase and neuropeptides on DRG sections, 2 weeks following L5 spinal nerve ligation (a well-characterized animal model of sympathetic pain). We found that basketed DRG neurons typically do not contain substance P, calcitonin gene-related peptide, galanin, neuropeptide tyrosine, or vasoactive intestinal polypeptide, and we conclude that if sympathetic baskets contribute to neuropathic pain, the involvement of these neuropeptides is unimportant.

Increase of preprotachykinin mRNA and substance P immunoreactivity in spared dorsal root ganglion neurons following partial sciatic nerve injury.

Complete sciatic nerve injury reduces substance P (SP) expression in primary sensory neurons of the L4 and L5 dorsal root ganglia (DRG), due to loss of target-derived nerve growth factor (NGF). Partial nerve injury spares a proportion of DRG neurons, whose axons lie in the partially degenerating nerve, and are exposed to elevated NGF levels from Schwann and other endoneurial cells involved in Wallerian degeneration. To test the hypothesis that SP is elevated in spared DRG neurons following partial nerve injury, we compared the effects of complete sciatic nerve transection (CSNT) with those of two types of partial injury, partial sciatic nerve transection (PSNT) and chronic constriction injury (CCI). As expected, a CSNT profoundly decreased SP expression at 4 and 14 days postinjury, but after PSNT and CCI the levels of preprotachykinin (PPT) mRNA, assessed by in situ hybridization, and the SP immunoreactivity (SP-IR) of the L4 and L5 DRGs did not decrease, nor did dorsal horn SP-IR decrease. Using retrograde labelling with fluorogold to identify spared DRG neurons, we found that the proportion of these neurons expressing SP-IR 14 days after injury was much higher than in neurons of normal DRGs. Further, the highest levels of SP-IR in individual neurons were detected in ipsilateral L4 and L5 DRG neurons after PSNT and CCI. We conclude that partial sciatic nerve injury elevates SP levels in spared DRG neurons. This phenomenon might be involved in the development of neuropathic pain, which commonly follows partial nerve injury.

Partial and complete sciatic nerve injuries induce similar increases of neuropeptide Y and vasoactive intestinal peptide immunoreactivities in primary sensory neurons and their central projections.

Partial nerve injury is more likely to cause neuropathic pain than complete nerve injury. We have compared the changes in neuropeptide expression in primary sensory neurons which follow complete and partial injuries to determine if these might be involved. Since more neurons are damaged by complete injury, we expected that complete sciatic nerve injury would simply cause greater increases in neuropeptide Y and vasoactive intestinal peptide than partial injury. We examined neuropeptide Y and vasoactive intestinal peptide immunoreactivities in L4 and L5 dorsal root ganglia, the dorsal horn of L4-L5 spinal cord, and the gracile nuclei of rats killed 14 days after unilateral complete sciatic nerve transection, partial sciatic nerve transection and chronic constriction injury of the sciatic nerves. In all three groups of rats, neuropeptide Y- and vasoactive intestinal peptide-immunoreactive neurons were increased in the ipsilateral L4 and L5 dorsal root ganglion when compared with the contralateral side. Most neuropeptide Y-immunoreactive neurons were of medium and large size, but a few were small. Neuropeptide Y-immunoreactive axonal fibers were increased from laminae I to IV, and vasoactive intestinal peptide-immunoreactive axonal fibers were increased in laminae I and II, of the ipsilateral dorsal horn of L4-L5 spinal cord. The increases of neuropeptide Y and vasoactive intestinal peptide immunoreactivities in the dorsal horn were similar among the three groups. However, only after constriction injury were some vasoactive intestinal peptide-immunoreactive neurons seen in the deeper laminae of the ipsilateral dorsal horn. Robust neuropeptide Y-immunoreactive axonal fibers and some neuropeptide Y-immunoreactive cells were seen in the ipsilateral gracile nuclei of all three groups of animals, but neuropeptide Y-immunoreactive cells were more prominent after constriction injury. Contrary to our expectations, partial and complete sciatic nerve injuries induced similar increases in neuropeptide Y and vasoactive intestinal peptide in lumbar dorsal root ganglion neurons and their central projections in the dorsal horn and the gracile nuclei two weeks after injury. Some neurons whose axons were spared by partial injury may also increase neuropeptide Y or vasoactive intestinal peptide expression. Altered neuropeptide release from these functional sensory neurons may play a role in neuropathic pain.

Differences in sympathetic innervation of mouse DRG following proximal or distal nerve lesions.

Nerve injury leads to novel sympathetic innervation of the dorsal root ganglion (DRG). We have hypothesized previously that the degenerating nerve increases the sympathetic sprouting in the DRG and pain after chronic sciatic constriction injury (CCI) by virtue of its influence on sensory and sympathetic axons spared by the injury. However, L5 spinal nerve ligation and transection (SNL) results in the complete isolation of the L5 DRG from the degenerating stump, yet sympathetic axons invade the ganglion, and sympathetically dependent pain develops. We investigated the role of Wallerian degeneration in both sympathetic sprouting and neuropathic pain in these two models of painful peripheral neuropathy by comparing responses of normal C57B1/6J and C57B1/Wlds mice in which degeneration is impaired. After CCI, Wlds mice, unlike 6J mice, did not develop thermal or mechanoallodynia or sympathetic innervation of the L5 DRG. After SNL, both strains developed mechanoallodynia and sympathetic sprouts in L5, but only 6J mice developed thermal allodynia. Observation of the origins of the invading sympathetic axons revealed that after CCI, sympathetics innervating blood vessels and dura (probably intact) sprouted into the ganglion, but after SNL sympathetics (probably axotomized) invaded from the injured spinal nerve. Based on these findings, we hypothesize that there are two mechanisms for sympathetic sprouting into DRG, differentially dependent on Wallerian degeneration. Analysis of pain behavior in these animals reveals that (i) mechanoallodynia and sympathetic innervation of the DRG tend to coincide and (ii) thermal allodynia and Wallerian degeneration, but not sympathetic innervation of the DRG tend to coincide.

Glial overexpression of NGF enhances neuropathic pain and adrenergic sprouting into DRG following chronic sciatic constriction in mice.

Adrenergic sprouts within axotomized dorsal root ganglia (DRG) may contribute to neuropathic pain, and may arise under the influence of nerve growth factor (NGF). We investigated effects of chronic constriction injury (CCI) on behavior and sprouting in mice in which NGF overexpression is driven by a glial protein (GFAP) promotor. GFAP-NGF mice were naturally hyperresponsive to radiant heat, and had enhanced ipsilateral responses to thermal and mechanical stimulation following CCI compared to wild-type mice. Sympathetic axons were already present in intact DRG of GFAP-NGF mice. Following CCI, sprouting in ipsilateral and to a lesser extent contralateral DRG occurred in both genotypes, but the sprout density 2 weeks post-lesion was much greater in GFAP-NGF mice. These results demonstrate a connection between the endogenous ectopic overexpression of NGF and (1) neuropathic pain behaviour and (2) sympathetic sprouting in the DRG.

Increase of calcitonin gene-related peptide immunoreactivity in the axonal fibers of the gracile nuclei of adult and aged rats after complete and partial sciatic nerve injuries.

Neuropeptide changes in primary sensory neurons are thought to be involved in the pathological mechanisms of neuropathic pain caused by peripheral nerve injuries. In this study, using immunocytochemistry, we observed that calcitonin gene-related peptide (CGRP) immunoreactive (IR) fibers were increased, qualitatively and quantitatively, in the injured side gracile nuclei of adult (2 months old) and aged (16 months old) rats 2 weeks following complete transection (CSNT) or chronic constriction injury (CCI) of sciatic nerves. This increase was more pronounced after CCI than after CSNT. In aged rats, the CGRP-IR fibers which appeared were dystrophic. In contrast to the increases which we saw in the gracile nucleus, after both types of injury there was a decrease in CGRP-IR in all laminae of the dorsal horn. The percentage of CGRP-IR DRG neurons was decreased after CSNT, but unchanged after CCI. We interpret our results in terms of local sprouting in the gracile nucleus and suggest that the increased response following CCI is due to the involvement of fibers from DRG neurons spared by the partial nerve injury. Increased CGRP release from spared afferents in the gracile nucleus might be important in neuropathic pain.

Increased activation of nuclear factor kappa B in rat lumbar dorsal root ganglion neurons following partial sciatic nerve injuries.

Nuclear factor kappa B (NFkappaB) is a transcription factor which can be activated by some neurotrophic factors and cytokines, and then translocated into the nucleus. We examined NFkappaB immunoreactivity (IR) in L4 and L5 dorsal root ganglion (DRG) cells of normal rats, and 2 weeks after complete sciatic nerve transection (CSNT), partial sciatic nerve ligation (PSNL) and chronic constriction injury (CCI). In the normal DRG, 45% of the neurons were NFkappaB-IR (IR in cytoplasm only or in both cytoplasm and nucleus). Only 18% were activated NFkappaB-IR cells (IR in both cytoplasm and nucleus). Two weeks after CSNT, PSNL and CCI, there was no significant difference in the percentages of NFkappaB-IR neurons between the ipsilateral and contralateral DRG. However, the percentages of the activated NFkappaB-IR neurons in the ipsilateral DRG of PSNL (30%) and CCI (33%) rats, but not in CSNT (24%) rats, were significantly increased, compared with the contralateral DRG. Ultrastructurally, NFkappaB-IR was localized to the endoplasmic reticulum and Golgi apparatus. In activated cells, IR was also observed in the nuclei. Two weeks after CCI, NFkappaB-IR was stronger in the axons and Schwann cells in the proximal stump of the injured sciatic nerves than in uninjured contralateral nerves. In some Schwann cells surrounding unmyelinated fibers, the nuclei were also NFkappaB-IR, suggesting that these cells were activated by CCI. NFkappaB activation increased in DRG neurons and Schwann cells 2 weeks following partial sciatic injuries, possibly in response to cytokines and neurotrophins produced by endoneurial cells in the partially injured nerve during Wallerian degeneration.

Immunolabelling of the cytoplasm and processes of apoptotic facial motoneurons following axotomy in the neonatal rat.

A polyclonal antibody intended to recognize c-Jun (Oncogene Science, c-jun/AP-1, Ab-2) has previously been shown to recognize an apparently novel "apoptosis-specific protein" (ASP) in the cytoplasm of cells undergoing apoptotic cell death in vitro. We have investigated whether this antibody would also serve as a reliable marker for apoptotic motoneurons in vivo. Following transection of the left facial nerve in anesthetized neonatal rat pups, which results in over 90% death of the facial motoneurons, we performed immunohistochemistry on frozen brain stem sections with Oncogene Science Ab-1 and Ab-2 antibodies which are raised against different peptide fragments of c-Jun. While Ab-1/c-Jun labelling was seen in the nuclei of the majority of axotomized motoneurons, Ab-2/ASP immunoreactivity was present only in scattered cells, all of which had characteristic apoptotic morphology. Furthermore, Ab-2/ASP immunoreactivity was cytoplasmic and frequently included the dendrites and axons of dying neurons. Some cerebellar granule cells undergoing postnatal developmental cell death were also Ab-2/ASP positive. The time course of the number of Ab-2/ASP-labelled motoneurons corresponded relatively closely with our previous data on DNA fragmentation in these cells, as assessed by an in situ end labelling (ISEL) technique. When facial nerve axotomy was performed at 7 and 14 days postnatum, resulting in reduced cell death, the number of Ab-2/ASP immunoreactive cells decreased correspondingly. Although the exact identity of the epitope recognized by Ab-2 is unclear, we conclude that, by labelling the cytoplasmic and neuritic components of apoptotic motoneurons, Ab-2/ASP immunohistochemistry is a valuable complementary technique to existing in situ methods based on the detection of fragmented DNA in the cell nucleus.

Normal and injury-induced sympathetic innervation of rat dorsal root ganglia increases with age.

In rats, partial injury to a peripheral nerve often leads to sympathetically maintained pain (SMP). In humans, this condition is especially apparent in the elderly. Nerve injury also causes perivascular sympathetic axons to sprout into the dorsal root ganglion (DRG), forming a possible anatomical substrate for SMP. Here, we describe the effects of chronic sciatic nerve constriction injury (CCI) in young (3 months) and old (16 months) rats on neuropathic pain behavior and on sympathetic sprouting in DRG. Behavioral tests assessed changes in thermal allodynia and hyperalgesia and in mechanical allodynia. We found that 1) sympathetic innervation of the DRG increased naturally with age, forming pericellular baskets mainly around large DRG neurons, and that sympathetic fibers were often associated with myelinated sensory axons; 2) sympathetic fiber density following CCI was also greater in old than in young rats; and 3) in old rats, thermal allodynia was less pronounced than in young rats, whereas thermal hyperalgesia and mechanical allodynia were more pronounced. These results highlight the possibility that sympathetic sprouting in the DRG is responsible for the sympathetic generation or maintenance of pain, especially in the elderly.

Effects of facial nerve injury on mouse motoneurons lacking the p75 low-affinity neurotrophin receptor.

When motoneuron axons in peripheral nerves are injured, the expression of the p75 low-affinity neurotrophin receptor (p75) increases in their cell bodies and axons, as well as in the Schwann cells undergoing Wallerian degeneration in the distal excised nerve segment. To understand the role of p75 in the events following nerve injury, we have examined the survival and regeneration of motoneurons in mice lacking the p75 receptor. In adult p75 (-/-) mice, functional recovery of whiskers movement following a facial nerve crush occurred slightly earlier than in p75 (+/+) mice, and some recovery of function over a 25-day interval following a nerve cut occurred more frequently in p75 (-/-) mice. Motoneuron profile numbers were slightly reduced in p75 (-/-) mice, and there were correspondingly fewer axons in the facial nerve. At 25 days following axotomy, profile survival in the adult p75 (-/-) mice was significantly improved compared to p75 (+/+) mice (mean 85%+/-standard error of the mean 3%, n = 11 vs. 67+/-5%, n = 11 in CD-1 mice and 68.0+/-4%, n = 6 in balb/c mice), and significantly more regenerating axons were present in the distal facial nerve. After axotomy on postnatal day 1, there was almost total loss of motoneuron profiles in the lateral facial nucleus in p75 (+/+) mice (1.7+/-0.3% remained, n = 5), while significantly more survived in p75 (-/-) mice (17 +/-2.5 %, n = 6). We conclude that expression of p75 in motoneurons or Schwann cells following facial nerve injury is not necessary for motoneuron survival or prompt regeneration of their axons; rather, p75 may increase their risk of dying.