Characterization of secondary hyperalgesia produced by topical capsaicin jelly--a new experimental tool for pain research.

Peripheral administration of the nociceptive agent capsaicin is used as an experimental tool to study neurophysiological and pharmacological aspects of the generation and control of pain. When investigating secondary hyperalgesia phenomena, current topical and intradermal capsaicin delivery methods have two key limitations. Intradermal injection can evoke severe chemogenic pain and both delivery methods produce an unstable area of dynamic mechanical allodynia. We present validity studies of a new preparation for capsaicin delivery that overcomes these limitations. The novel capsaicin formulation consists of a water-based semisolid jelly preparation containing 1% capsaicin which is applied topically under adhesive-free occlusion to a small area of the skin. We demonstrate that in healthy human subjects this model evokes areas of flare, punctate hyperalgesia and mechanical allodynia which are equivalent to established models and that these areas are stable over time and reproducible on repeat experiments. The jelly formulation evokes only minimal chemogenic pain and, as the preparation remains in situ throughout the study providing constant capsaicin exposure, a stable area of dynamic mechanical allodynia is produced. These validation studies show that this novel capsaicin administration method is a practical, reliable and viable tool for investigating experimental secondary hyperalgesia.

Peripheral neuropathic pain--a multidimensional burden for patients.

The present study was undertaken to assess the health-related quality of life (HRQoL) and burden of illness due to pain and its treatment for patients with peripheral neuropathic pain (PNP). It is the first step in finding reliable instruments/targets to evaluate treatment outcome in this patient population. Study population consisted of 126 patients suffering from neuropathic pain due to a peripheral nerve or root lesion, recruited from two multidisciplinary pain clinics. HRQoL was examined using Short Form 36 (SF-36) Health Survey and Nottingham Health Profile (NHP). Pain intensity in four categories (at rest and evoked by movement, touch and cold) was rated on a visual analogue scale (VAS). Degree of discomfort from pain and 25 symptoms related to pain and side-effects was also assessed. Reduction in workload due to pain was recorded, as was the pain relief from previous and current treatments and the reasons for discontinuing previous treatments. All dimensions in SF-36 and NHP were significantly impaired. SF-36 was a valid instrument for describing the impact of pain on the HRQoL of patients with PNP. NHP had a lower reliability but has other advantages that might be of importance. Many patients experienced poor pain relief from ongoing pain treatments. Most previous treatments were discontinued owing to lack of efficacy and/or severe side-effects. Many patients experienced a high intensity of at least one type of pain; median VAS for the highest pain intensity score of each patient (any type of pain) was 74/100. Besides pain, patients were most bothered by difficulty in sleeping, lack of energy, drowsiness, difficulty in concentrating and dry mouth. Employment status was reduced owing to pain in 52% of the patients. The intense pain, other troublesome symptoms, limited efficacy and tolerability of available treatments, together with the impaired health and reduced work status, amount to a substantial burden for patients with PNP.

Sensory threshold changes without initial pain or alterations in cutaneous blood flow, in the area of secondary hyperalgesia caused by topical application of capsaicin in humans.

Changes in von Frey hair perception, pricking pain, and vibration thresholds were examined in six healthy human adults, in the zone of secondary hyperalgesia, 45 min following the topical application of capsaicin at concentrations of 0.05 and 0.1 mg/ml. In two of these subjects, cutaneous blood flow was monitored at 10-min intervals, before, during and after capsaicin application, using laser Doppler perfusion imaging. Thresholds for all three parameters were significantly reduced after capsaicin treatment, in a dose-dependent manner. However, there was no visible skin flare, and no change in cutaneous blood flow at these doses of capsaicin. The effects on von Frey perception threshold and vibration threshold have not been demonstrated previously, and may be indicative of central changes, initiated by afferent fibres (presumably C fibres) that are not vasoactive.

Effects of dextromethorphan in clinical doses on capsaicin-induced ongoing pain and mechanical hypersensitivity.

The analgesic properties of the noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist dextromethorphan, available for clinical use as an antitussive, have been studied in the human capsaicin pain model to determine a possible clinical effect on pain due to central sensitization. Ninety milligrams dextromethorphan or vehicle was given orally to ten volunteers, each at two different occasions in a double-blind fashion, prior to an intradermal injection of 300 micrograms capsaicin. Ongoing pain, pain evoked by von Frey filament stimulation, and pressure pain thresholds were assessed before and after the capsaicin injection. The area in which von Frey filament stimulation evoked pain was mapped after the capsaicin injection. There were no significant group effects on ongoing pain, or on von Frey or pressure hypersensitivity. There was also no significant effect on the area of mechanical hypersensitivity. These results show that clinical doses of dextromethorphan do not effect ongoing or mechanically evoked pain after capsaicin injection.

Peripherally administrated morphine attenuates capsaicin-induced mechanical hypersensitivity in humans.

We examined the hypothesis that peripheral morphine can modulate pain and hyperalgesia/allodynia in the human capsaicin model. Subcutaneous injections of 1 mL morphine (1 mg/mL) in one arm and of 1 mL 0.9% saline in the other arm were made prior to bilateral intradermal injections of 50 microL (6 mg/mL) capsaicin. All injections were made on the volar aspect of the arm. Before and after the capsaicin injections, spontaneous pain and pain evoked by repetitive von Frey filament stimulation was rated on a numerical rating scale; furthermore, pressure pain thresholds were determined. The area in which von Frey filament stimulation evoked pain and the area of visible flare were mapped after the capsaicin injection. Capsaicin injection resulted in spontaneous pain on the saline-injected side not significantly different from that on the morphine-injected side. However, capsaicin injections gave rise to significantly less pain evoked by mechanical stimuli, as well as to a significantly smaller area of mechanical hypersensitivity, on the morphine-injected side compared with the saline-injected side. These results suggest that morphine can modulate sensitization mechanisms involved in the development of capsaicin-induced mechanical hypersensitivity.

Peripheral alpha-adrenoreceptors are involved in the development of capsaicin induced ongoing and stimulus evoked pain in humans.

While the sympathetic nervous system seems to be involved in some pain states, the mechanisms linking the sensory and sympathetic nervous system are unclear. In this study the possible involvement of peripheral alpha-adrenoreceptors in the development of capsaicin induced ongoing pain and mechanical hypersensitivity was examined in humans. Intradermal capsaicin injections in the volar aspect of the arm gave rise to ongoing burning pain and dysesthesia as well as mechanical hypersensitivity. Ongoing pain and pain evoked by von Frey filament stimulation was rated on a numerical rating scale after intradermal capsaicin injection. The area of skin in which von Frey filament stimulation evoked pain was measured. A subcutaneous injection of phentolamine (alpha-adrenoreceptor antagonist) on one side and saline on the other side prior to the capsaicin injection was done to evaluate the role of the peripheral alpha-adrenoreceptors in development of capsaicin induced sensory symptoms and signs. Significantly less ongoing and evoked pain developed on the phentolamine injected side compared to the saline side, the latter in the area adjacent to the capsaicin injection (primary zone) and well outside the area of flare (secondary zone). The area in which pain could be evoked on the phentolamine injected side was restricted to the area of flare and was significantly smaller than on the saline injected side. Mechanical stimulation gave rise to aftersensation and radiation of pain on the saline injected side in all subjects but only in one case on the phentolamine injected side. Peripheral alpha-adrenoreceptors thus seem to be involved in functional changes of primary afferents which contribute to ongoing pain and mechanical stimulus evoked pain.

Delayed sympathectomy after a prolonged hyperalgesia results in a subsequent enhanced acute hyperalgesic response.

We report on the ability of a delayed sympathectomy after a prolonged hyperalgesia to result in a subsequent enhanced hyperalgesic response. Sympathectomy was performed one day after injection of prostaglandin E2 plus rolipram, which induces a prolonged sympathetically-maintained hyperalgesia [Aley K. O. and Levine J. D. (1995) Eur. J. Pharmac. 273, 107-112]. The duration of hyperalgesia produced by a subsequent injection of prostaglandin E2 or prostaglandin E2 plus rolipram was then assessed. Lumbar surgical sympathectomy, done on day 2 or 3, prevented prostaglandin E2 plus rolipram-induced prolonged hyperalgesia from developing when they were injected five days after surgery, similar to the previous report of the effect of prior sympathectomy to block the rolipram enhancement [Aley K. O. and Levine J. D. (1995) Eur. J. Pharmac. 273, 107-112]. Sympathectomy done five days after injection of prostaglandin E2 plus rolipram, however, paradoxically prolonged (at least 10 days) hyperalgesia induced by a subsequent prostaglandin E2 plus rolipram injection, a duration much greater than that seen after prostaglandin E2 plus rolipram in naive animals. To determine the roles of prostaglandin E2 and rolipram in the prolongation of hyperalgesic response after delayed sympathectomy, rats were treated with either prostaglandin E2 or rolipram prior to sympathectomy. Prostaglandin E2 or rolipram alone were also administered five days after the sympathectomy. It was found that sympathectomy done five days after first injecting either prostaglandin E2 or rolipram alone did not produce enhanced hyperalgesic response. These data suggest that induction of a prolonged state of mechanical hyperalgesia causes time-dependent alterations in the sympathetic control of peripheral nociceptive mechanisms such that sympathectomy can lead to enhanced hyperalgesic response. These findings may be relevant to post-sympathectomy pain, a clinical entity for which there has been no available animal models.

Variation in the anatomy of the lumbar sympathetic chain in the rat.

The rat is often used when the sympathetic nervous system contribution to various physiological and pathological processes is studied. These experiments require a detailed knowledge of the lumbar sympathetic chain anatomy since the macroscopic anatomy of the L2 and L3 levels of the sympathetic chain, which innervate a major portion of the hindleg, is highly variable. We have performed a detailed study of the anatomy of the lumbar sympathetic chain in 245 Sprague-Dawley rats. Through anatomical characterization of the L2 and L3 sympathetic ganglia white and gray ramus communicants, our study provides an anatomical guide for studies of the function of the lumbar sympathetic chain in the rat.

Involvement of the sympathetic postganglionic neuron in capsaicin-induced secondary hyperalgesia in the rat.

The involvement of the sympathetic postganglionic neuron in secondary hyperalgesia was evaluated using a model of secondary hyperalgesia induced by a small intradermal injection of capsaicin in the rat, a procedure known to produce mechanical hyperalgesia/allodynia in humans. Capsaicin injection into the glabrous skin of the hind paw led to increased sensitivity to mechanical stimulation with von Frey filaments at the injection site (i.e. primary hyperalgesia) as well as in an area of the hind paw remote from the site of injection (i.e. secondary hyperalgesia). Surgical removal of the sympathetic postganglionic neurons innervating the hind paw plantar skin before the capsaicin injection prevented secondary hyperalgesia. However, decentralization of the sympathetic postganglionic neurons subserving the hind paw did not effect secondary hyperalgesia. Phentolamine, an alpha-adrenergic receptor antagonist, as well as prazosin, an alpha 1-adrenergic receptor antagonist, given systemically, both blocked the development of secondary hyperalgesia. Yohimbine, an alpha 2-adrenergic receptor antagonist, was without effect. Prazosin also blocked the development of secondary hyperalgesia when given intradermally at the site of capsaicin injection. Activation of C-fibres with capsaicin induces secondary hyperalgesia, which is sympathetic postganglionic neuron-dependent. This sensory-sympathetic interaction is, however, independent of preganglionic sympathetic outflow and seems to be mediated by an alpha 1-adrenergic mechanism. Sensory-sympathetic interaction appears to take place in the area of capsaicin-induced C-fibre nociceptor activation.

Sensory and sympathetic contributions to nerve injury-induced sensory abnormalities in the rat.

Peripheral neuropathy can be associated with a variety of symptoms, including spontaneous unpleasant sensations and pain, as well as increased sensitivity to sensory stimuli. A peripheral neuropathy model involving an L5 spinal nerve lesion in male rats has been used to gain insight into the mechanisms that underlie symptoms that develop after nerve injury. This model was used to study the involvement of sensory fibres, the sympathetic postganglionic neuron and the role of nerve growth factor in the induction and maintenance of altered sensory function in the nerve territory of the intact L4 spinal nerve. Sensory testing was done with calibrated von Frey filaments and a radiant heat apparatus [Hargreaves K. et al. (1988) Pain 32, 77-88] and the occurrence of abnormal spontaneous behaviour was recorded. L5 spinal nerve resection produced increased mechanical and heat sensitivity as well as abnormal spontaneous behaviours. Surgical sympathectomy at the L5 but not at the L4 spinal nerve level alleviated all sensory abnormalities. However, a lesion of preganglionic fibres to the L5 level had no significant effect on sensory abnormalities. Thus, sympathetic postganglionic neurons at the level of spinal nerve injury can contribute to neuropathy symptoms independent of input from preganglionic neurons. Postganglionic sympathetic nerve crush alone led to increased mechanical sensitivity but not to increased heat sensitivity nor to abnormal spontaneous behaviour, further emphasizing the role of sympathetic postganglionic neuron changes for the development of increased mechanical sensitivity. An L5 spinal nerve resection in rats treated neonatally with capsaicin induced increased mechanical sensitivity which was slower in onset and lower in magnitude than that in untreated littermates and was abolished by postganglionic sympathectomy. Nerve growth factor perfused onto the cut L5 spinal nerve also markedly delayed the onset of increased mechanical sensitivity. Two pathophysiological mechanisms leading to central changes may be necessary to produce altered sensations in this model: (i) ongoing activity in C-fibres, independent of sympathetic postganglionic neuron activity and (ii) activity in sensory fibres modulated by a sensory-sympathetic interaction in the injured spinal nerve or dorsal root ganglion. The sympathetic postganglionic neuron contribution is independent of preganglionic sympathetic outflow from the central nervous system, suggesting a novel mechanism by which sympathetic efferent terminals can regulate sensory fibre activity. A contribution of a loss of neurotrophic factors to the sympathetic postganglionic neuron following nerve lesion is also suggested to contribute to the symptoms induced by the spinal nerve lesion.

The innervation of the mystacial pad of the rat as revealed by PGP 9.5 immunofluorescence.

The innervation of the mystacial pad in the rat was investigated with the aid of antihuman protein gene product (PGP) 9.5 immunofluorescence. PGP 9.5 is ubiquitin carboxyl-terminal hydrolase, which is distributed throughout neuronal cytoplasm. This technique revealed all previously known innervation as well as a wide variety of small-caliber axons and some endings of large-caliber afferents that had not been observed before. Newly revealed innervation affiliated with vibrissal-follicle sinus complexes included 1) fine-caliber, radially oriented processes in the epidermal rete ridge collar; 2) a loose network of fine-caliber, circumferentially arrayed processes in the centrifugal part of the mesenchymal sheath at the level of the ring sinus; 3) a loose haphazard network of fine-caliber and medium-caliber processes in the mesenchymal sheath and among the trabeculae of the cavernous sinus; 4) a loose network of circumferentially arrayed processes within the mesenchymal sheath of the cavernous sinus and in close proximity to the basement membrane; 5) a dense network of reticular-like endings provided by large-caliber afferents to the mesenchymal sheath in the upper part of the cavernous sinus; and 6) fine-caliber innervation to the dermal papilla at the base of all vibrissal shafts. In the intervibrissal skin, a dense distribution of fine-caliber individual and clustered profiles was detected in the epidermis. In addition to previously known innervation, Merkel endings were consistently observed in the epidermis at the mouths of guard hairs, loose networks of fine-caliber axons were found around the necks of occasional guard hairs, and fine-caliber profiles were frequently affiliated with vellus hairs. Vascular profiles were heavily innervated throughout the dermis. Axons and motor end plates of the facial nerve innervation to papillary muscles also were labeled. Transection of the infraorbital nerve eliminated all but the facial nerve innervation. Unilateral removal of the superior cervical ganglion eliminated the innervation to the dermal papillae but caused no other noticeable reduction. PGP 9.5-like immunofluorescence was also moderately expressed in apparent Schwann cells, in Merkel cells only in the external root sheath of vibrissal follicles, and in apparent dendritic and/or Langerhans cells usually located in the epidermis and occasionally in the follicles. PGP 9.5-like immunofluorescence persisted in highly vacuolated profiles along the usual courses of medium to large-caliber axons 2 weeks after nerve transection. The possible functional role of the newly discovered innervation is considered along with that of previously identified afferents.

Time course and characteristics of the capacity of sensory nerves to reinnervate skin territories outside their normal innervation zones.

Factors involved in the outcome of regeneration of the saphenous nerve after a cut or crush lesion were studied in adult rats with electrophysiological recordings of low-threshold mechanoreceptor activity and plasma extravasation of Evans blue after electrical nerve stimulation that activated C fibers. In the first series of experiments, saphenous and sciatic nerve section was combined with anastomosis of the transected proximal end of the saphenous nerve to the distal end of the cut tibial nerve. Regeneration of saphenous nerve fibers involved in plasma extravasation and low-threshold mechanoreceptor activity in the glabrous skin was observed 13 weeks after nerve anastomosis. Substance P-, calcitonin gene-related peptide-, and protein gene product 9.5 (PGP-9.5)-immunoreactive (IR) thin epidermal and dermal nerve endings, as well as coarse dermal PGP-9.5-IR nerve fibers and Meissner corpuscles and Merkel cell-neurite-like complexes, were observed in the reinnervated glabrous skin at this time. In a second series of experiments, the time course of the regeneration of saphenous nerve axons to the permanently sciatic-nerve-denervated foot sole was examined. Saphenous-nerve-induced plasma extravasation and low-threshold mechanoreceptor activity in the saphenous nerve were found in the normal saphenous nerve territory 2, 3, 4, and 6 weeks after sciatic nerve cut combined with saphenous nerve crush in the left hindlimb. Saphenous-nerve-induced plasma extravasation was also present in the glabrous skin normally innervated by the sciatic nerve 3, 4, and 6 weeks after the sciatic cut/saphenous crush lesion. However, no low-threshold mechanoreceptor activity was detected in the saphenous nerve when the glabrous skin area was stimulated. In a third series of experiments, the fate of the expansion of the saphenous nerve territory after saphenous nerve crush was examined when the crushed sciatic nerve had been allowed to regenerate. Nerve fibers involved in plasma extravasation were observed in the glabrous skin of the hindpaw after saphenous nerve, as well as after tibial nerve, C-fiber stimulation 3, 12, and 43 weeks after the saphenous crush/sciatic crush lesion. Low-threshold mechanoreceptors from the regenerated saphenous nerve, which primarily innervates hairy skin, seem to be functional in the glabrous skin if the axons are guided by the transected tibial nerve by anastomosis. Furthermore, the results indicate that fibers from the regenerating saphenous nerve that have extended into denervated glabrous skin areas can exist even if sciatic nerve axons are allowed to grow back to their original territory.

Collateral reinnervation and expansive regenerative reinnervation by sensory axons into "foreign" denervated skin: an immunohistochemical study in the rat.

Immunohistochemistry has been used to study, the capacity of different types of sensory axons in the saphenous nerve to extend into denervated glabrous skin territory after a chronic sciatic nerve lesion. In this study, the extension of the intact or regenerating thin peptidergic and coarse saphenous nerve fibres in adult and neonatal rats was determined. Substance P (SP) and calcitonin gene-related peptide (CGRP) antibodies were used as markers for thin axons and neurofilament (NF) antibodies for coarse axons. In addition, S-100 protein (S-100) antibodies, which primarily stain Schwann cells associated with myelinated axons, as well as innervated lamellated cells of Meissner corpuscles, were used. After a chronic sciatic nerve lesion in adult rats, thin dermal and epidermal SP-immunoreactive (IR) and CGRP-IR saphenous nerve fibres were present in an area lateral to that normally innervated by the saphenous nerve in the foot sole. In neonatally lesioned animals, thin dermal and epidermal SP-IR and CGRP-IR, as well as coarse dermal NF-IR fibres and S-100-IR cells, all of which derived from the saphenous nerve, were found in the sciatic nerve territory. In addition, some dermal SP-IR and CGRP-IR fibres were transiently present in the lateral part of the foot sole. After chronic sciatic nerve lesion and a concomitant crush injury of the saphenous nerve in adults or neonatals, thin dermal and epidermal SP-IR and CGRP-IR fibres, as well as coarse dermal NF-IR fibres and S-100-IR cells, were found in the innervation area normally occupied by the sciatic nerve. After a sciatic nerve cut and a concomitant crush injury of the saphenous nerve in adult rats, the SP-IR and CGRP-IR fibres, as well as the NF-IR fibres and S-100-IR cells were restricted to the medial part of this area. After a sciatic nerve cut and a concomitant crush injury of the saphenous nerve in neonatal rats, a few thin dermal SP-IR and CGRP-IR fibres were found in the lateral part of the foot sole as well. The findings of the present study together with those of previous morphological studies indicate that intact thin axons from the saphenous nerve, including those exhibiting peptide immunoreactivity, but not coarse saphenous axons, are capable of extending into "foreign" denervated glabrous skin after chronic sciatic nerve injuries. In neonatally sciatic-nerve-injured animals, both groups of axons spread from the intact saphenous nerve into the sciatic nerve territory.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of substance P and calcitonin gene-related peptide containing nerve fibers in maintaining fungiform taste buds in the rat after a chronic chorda tympani nerve injury.

Taste buds in the anterior part of the tongue of adult rats were denervated by unilateral resection of the chorda tympani nerve in the middle ear. Three months later one group of animals was perfused and their tongues were processed for demonstration of substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactivity. Fungiform taste buds found on the denervated side showed increased numbers of intragemmal SP- and CGRP-immunoreactive (IR) fibers compared to the normal side. Compared to the normal side, the number of taste buds appeared to be fewer on the denervated side. Moreover, taste buds on this side seemed to be only partially restored. Another group of animals was given the neurotoxin capsaicin which causes a depletion of SP and CGRP from sensory axons. The animals were perfused 2 or 3 weeks after the capsaicin treatment, and their tongues prepared for SP and CGRP immunohistochemistry or for histological examination of taste buds. Very few SP- and CGRP-IR fibers were present in capsaicin-treated animals. In these animals almost all fungiform taste buds and papillae on the chorda tympani-injured side disappeared. In contrast, normal numbers of taste buds were still present on the contralateral side where the chorda tympani innervation remained intact. It is conceivable that taste buds on the chorda tympani-innervated part of the tongue, deprived of the normal chorda tympani-innervation, can regenerate and become reinnervated by SP- and CGRP-containing fibers, and that these are essential for partially restoring and maintaining the structure of the denervated taste buds and the fungiform papillae.

Expansion of innervation territory by afferents involved in plasma extravasation after nerve regeneration in adult and neonatal rats.

The capacity of the saphenous nerve for collateral sprouting was examined by electrophysiological recordings of the activity of low threshold mechanoreceptors and plasma extravasation after C-fiber stimulation in rats. When the sciatic nerve was sectioned neonatally or in adults little evidence was obtained for collateral sprouting of either mechanoreceptors or fibers involved in plasma extravasation in the intact saphenous nerve. In rats where the sciatic nerve was sectioned and the saphenous nerve was crushed either neonatally or in adults, expansive regenerative reinnervation by thin fibers, but not mechanoreceptors, was observed particularly in glabrous skin. Saphenous crush alone did not cause expansive regenerative reinnervation. The results indicate that much of the collateral sprouting or regenerative reinnervation of the skin observed in morphological studies may represent the presence of fibers not responding to the stimuli used in the present study. It is also suggested that some observations of collateral sprouting may represent changes in responsiveness to stimulation of skin areas with overlapping innervation territories.

Studies of normal and expansive cutaneous innervation territories of intact and regenerating C-fibres in the hindlimb of the rat.

Two sets of experiments were carried out in order to evaluate the unmyelinated (C) fibre innervation of the hindlimb of rats. In the first experiment the normal innervation territory of the various nerves to the skin in the hindfoot was examined by plasma extravasation of Evans blue after antidromic nerve stimulation. Considerable overlap was found in the territories of nerves on the dorsum of the toes and just proximal to the toes. In the second experiment the capacity of C-fibres in the saphenous nerve for growth into deafferented skin was examined. In rats in which the sciatic nerve was previously sectioned, the innervation territory of the intact saphenous nerve expanded slightly into that of the sciatic in about 20% of the cases by "collateral sprouting". When the sciatic nerve section was combined with ipsilateral saphenous nerve crush, the regenerating C-fibres in the saphenous nerve innervated the sciatic territory in almost 100% of cases, a process we termed "expansive regenerative reinnervation". We conclude that the existence of overlapping C-fibre innervation territories need to be considered in studies of "collateral sprouting". However, regenerating C-fibres can innervate foreign deafferented skin.

Expansion of spinal cord primary sensory afferent projection following combined sciatic nerve resection and saphenous nerve crush: a horseradish peroxidase study in the adult rat.

Transganglionic transport of horseradish peroxidase was used to study the potential for collateral sprouting of saphenous nerve afferent fibers in the lumbar dorsal horn of the adult rat following (1) combined unilateral saphenous nerve crush and ipsilateral sciatic nerve resection, (2) unilateral saphenous nerve crush, and (3) unilateral sciatic nerve resection. The saphenous nerve on the nonlesioned contralateral side served as control. Eight weeks after the lesion(s) the animals were subjected to bilateral application of horseradish peroxidase to the saphenous nerves. The distribution of the ensuing labeling in the superficial dorsal horn was subsequently mapped. Combined saphenous nerve crush and sciatic nerve resection resulted in expansion of the saphenous nerve projection area in the dorsal horn when compared to the nonlesioned control side (mean = 13%, P less than 0.05). No expansion of the saphenous nerve projection was found following isolated saphenous nerve crush or sciatic nerve resection, respectively (P greater than 0.05). The findings indicate that in the adult rat, central processes of primary sensory neurons which are regenerating their peripheral processes can extend collateral sprouts into adjacent projection areas in the superficial dorsal horn subjected to previous deafferentation by peripheral nerve resection.

Collateral reinnervation of taste buds after chronic sensory denervation: a morphological study.

Peripheral transganglionic transport of horseradish peroxidase (HRP) was used to label afferent fibers in the taste buds and lingual epithelium 2-12 weeks after chronic chorda tympani or combined chorda tympani-lingual nerve lesions. From 4-12 weeks after a chronic chorda tympani lesion, taste buds could be found. These were innervated by fibers from the ipsilateral lingual nerve. From 8-12 weeks after a chronic chorda tympani-lingual nerve lesion, nerve fibers from the contralateral lingual nerve could be found in a few taste buds on the denervated side of the tongue. Thus, collateral sprouting took place over the midline in this instance. These findings indicate that intact gustatory axons do not sprout into denervated taste buds, but trigeminal fibers in the lingual nerve do have this ability.

Collateral sprouting of sensory axons in the hairy skin of the trunk: a morphological study in adult rats.

The capacity of sensory axons in the hairy skin of adult rats to extend branches into adjacent denervated skin has been studied by anterograde tracing with wheat germ agglutinin-horseradish peroxidase conjugate. In one series of experiments the Th10 intercostal nerve area was isolated and the distribution of sensory axons from the lateral cutaneous nerve was examined in control experiments and at various times after the denervation. In a second series of experiments, the entire Th10 was isolated, and the caudal extension of sensory axons from the Th10 spinal nerve was examined in control experiments and at various times after the denervation. The findings indicate that thin as well as coarse cutaneous sensory nerve axons can extend collateral sprouts within their 'own' dermatome as well as outside their normal segmental territory. Thus the dermatomal border does not seem to be a limit for collateral sprouting of coarse sensory nerve axons.