Nociceptive Axons Research Articles

Evidence that endogenous beta nerve growth factor is responsible for the collateral sprouting, but not the regeneration, of nociceptive axons in adult rats.

A key role has not yet been identified for beta nerve growth factor (NGF) in the growth responses that continue to be expressed in the sensory neurons of adult animals. We have now examined the effects of daily administration to adult rats (and in a few experiments, mice) of antiserum to NGF on (i) the collateral sprouting of undamaged nociceptive nerves that occurs into denervated adjacent skin and (ii) the regeneration of cutaneous sensory axons that occurs after they are damaged. The results were unexpected. All collateral sprouting was prevented and that already in progress was halted; sprouting resumed when treatment was discontinued. In contrast, the reestablishment, and even enlargement, of cutaneous nerve fields by regenerating axons was unaffected by anti-NGF treatment, even after dorsal rhizotomy was done to eliminate any central trophic support. In denervated skin, regenerating and collaterally sprouting axons utilized the same cellular pathways to establish functionally identical fields, thus displaying apparently identical growth behaviors, yet anti-NGF treatment clearly distinguished between them. We suggest that endogenous NGF is responsible for the collateral sprouting of nociceptive axons, probably reflecting an ongoing function of NGF in the regulation of their fields. This demonstration in the adult sensory system of a defined role for NGF in nerve growth could apply to nerve growth factors generally in the adult nervous system. The regeneration, however, of nociceptive axons (and nonnociceptive one) is not dependent on NGF.

Calcitonin gene-related peptide (CGRP) as a selective label of nociceptor axons

Calcitonin gene-related peptide (CGRP) as a selective label of nociceptor axons

Has the amount of spontaneous electrical activity in experimental neuromas been overestimated?

Previous studies of experimental neuromas have indicated that some axons terminating in the neuroma exhibit both spontaneous and mechanosensitive discharges. Since these spontaneous discharges appear to occur in potentially nociceptive axons (A delta and C fibers), it has been speculated that this activity may relate to pain that occurs after peripheral nerve injury. Recent results from our laboratory have revealed several possible sources of error in prior electrophysiological studies of neuromas. Most notably, gallamine, a muscle-paralyzing agent that has been used in the majority of previous studies of experimental neuromas, has profound potassium-channel-blocking properties that may increase spontaneous activity in damaged axons. The present study was conducted to re-evaluate the incidence of spontaneous activity in experimental neuromas, and the fiber types involved in these discharges. A group of 44 male Sprague-Dawley rats underwent unilateral saphenous axotomy 1-8 weeks prior to acute neurophysiological recording experiments, and 6 additional rats underwent acute control recording procedures only. Recording was performed in all animals using a modification of the microfilament recording technique to determine the conduction velocities (CVs) and origins of spontaneously discharging axons. A thorough search for spontaneous discharges was made in each nerve both before and after the administration of gallamine. Spontaneous activity was rare in acutely severed saphenous nerve and was not significantly affected by gallamine administration. In rats with 1- to 4-week-old experimental saphenous neuromas, spontaneous activity was rare but was increased by a factor of 12.75 after gallamine treatment. Gallamine administration produced significantly more of both A alpha beta and A delta activity, compared to control recordings. No spontaneous C-fiber activity was found originating in neuromas either before or after gallamine. C-fiber spontaneous discharges in the apparently isolated saphenous nerve segment had receptive fields in fascia, superficial vasculature, and hairy skin of the medial hindlimb. Our conclusions are as follows: (1) Neuromas exhibit only rare spontaneous discharges unless exposed to potassium-channel-blocking agents; (2) all C-fiber activity recorded in saphenous nerve with a distal neuroma is derived from vascular, fascial, and other receptive fields rather than from the neuroma; (3) these data are consistent with known clinical phenomena in that neuromas are not usually spontaneously painful.

Peptidergic nociceptive axon visualization in whole-mount preparations of cornea and tympanic membrane in rat

A whole-mount preparation is described for visualizing unmyelinated peptide immunoreactive axons in two specialized tissues, thin enough for tracing axons to their terminal knobs. These tissues, the cornea and the mucosal surface of the tympanic membrane, area known to possess specialized nociceptor innervation and can be used for selecting sensory endings labeled by peroxidase reaction product and embedded in plastic for more detailed analysis. Rat calcitonin gene-related peptide antibody proved a particularly robust primary antibody found in a substantial proportion of sensory unmyelinated axons in a variety of fixation and preparative conditions.

Collateral reinnervation of sweat glands.

The collateral reinnervation of mouse sweat glands has been studied by a method that allows serial evaluation of the course of reinnervation in intact animals. The method is based on the finding that the activation of secretion from newly denervated sweat glands by pilocarpine or nerve stimulation is completely absent seven days after nerve section but returns with reinnervation. These characteristics allowed serial detection of footpad sweat glands newly reinnervated by collateral sprouting of the remaining intact saphenous nerve after section of the sciatic nerve. The number of saphenous innervated glands increased five- to sevenfold and the total saphenous sweat territory was greatly expanded across the volar surface of the hind paw. There was less enlargement when the sciatic nerve was allowed to regenerate and participate in reinnervation of sweat glands. None of the reinnervated glands were dually innervated by saphenous and sciatic nerves, as is the case in normal glands. When the saphenous nerve was sectioned after saphenous collateral sprouting was complete and after sciatic regeneration had innervated an apparent maximal number of glands, the sciatic nerve reacted by advancing farther into the formerly enlarged saphenous territory and re-reinnervated many of the glands. Collateral sprouting by sudomotor axons is more abundant and more widely dispersed than reported for larger nerve fibers to skeletal muscle and to low-threshold mechanoreceptors. It more closely resembles sprouting of nociceptive axons.

Regenerative synaptoneogenesis in the Mammalian spinal cord: dynamics of synaptochemical restoration in the Rolando Substance after transganglionic degenerative atrophy.

Crush injury of the sciatic nerve, that results in Wallerian degeneration of axons in the peripheral stump, induces, within 10-14 days, transganglionic degenerative atrophy of central terminals of primary nociceptive neurons in the ipsilateral substantia gelatinosa Rolandi of the segmentally related region of the spinal cord. Transganglionic degenerative atrophy is characterized by disappearance of fluoride-resistant acid phosphatase (FRAP) from the Rolando substance, normally exerted by primary nociceptive terminals. From the 40th postoperative day on, FRAP reaction starts to reappear in the formerly depleted Rolando substance. Restoration of FRAP reactivity reflects regenerative sprouting of formerly atrophied primary nociceptive terminals. Growth cones of primary nociceptive axons establish synapses with dendritic growth cones of substantia gelatinosal gelatinosal cells. Synaptoneogenesis in the Rolando substance follows medio-lateral and caudo-rostral gradients.

Wanted: Old Instruments for Extracting Teeth

Musculoskeletal pain affects nearly half of all adults, most of whom are vitamin D deficient. Previous findings demonstrated that putative nociceptors (“pain-sensing” nerves) express vitamin D receptors (VDRs), suggesting responsiveness to 1,25-dihydroxyvitamin D. In the present study, rats receiving vitamin D-deficient diets for 2–4 weeks showed mechanical deep muscle hypersensitivity, but not cutaneous hypersensitivity. Muscle hypersensitivity was accompanied by balance deficits and occurred before onset of overt muscle or bone pathology. Hypersensitivity was not due to hypocalcemia and was actually accelerated by increased dietary calcium. Morphometry of skeletal muscle innervation showed increased numbers of presumptive nociceptor axons (peripherin-positive axons containing calcitonin gene-related peptide), without changes in sympathetic or skeletal muscle motor innervation. Similarly, there was no change in epidermal innervation. In culture, sensory neurons displayed enriched VDR expression in growth cones, and sprouting was regulated by VDR-mediated rapid response signaling pathways, while sympathetic outgrowth was not affected by different concentrations of 1,25-dihydroxyvitamin D. These findings indicate that vitamin D deficiency can lead to selective alterations in target innervation, resulting in presumptive nociceptor hyperinnervation of skeletal muscle, which in turn is likely to contribute to muscular hypersensitivity and pain.