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Work-related musculoskeletal disorders associated with intense repetitive tasks are highly prevalent. Painful symptoms associated with such disorders can be attributed to neuropathy. In this study, we characterized the neuronal discharge from the median nerve in rats trained to perform an operant repetitive task. After 3-weeks of the task, rats developed pain behaviors and a decline in grip strength. Ongoing activity developed in 17.7% of slowly conducting neurons at 3-weeks, similar to neuritis. At 12-weeks, an irregular high frequency neuronal discharge was prevalent in >88.4% of slow and fast conducting neurons. At this time point, 8.3% of slow and 21.2% of fast conducting neurons developed a bursting discharge, which, combined with a reduction in fast-conducting neurons with receptive fields (38.4%), is consistent with marked neuropathology. Taken together, we have shown that an operant repetitive task leads to an active and progressive neuropathy that is characterized by marked neuropathology following 12-weeks task that mainly affects fast conducting neurons. Such aberrant neuronal activity may underlie painful symptoms in patients with work-related musculoskeletal disorders. PERSPECTIVE: Aberrant neuronal activity, similar to that reported in this study, may contribute to upper limb pain and dysfunction in patients with work-related musculoskeletal disorders. In addition, profiles of instantaneous frequencies may provide an effective way of stratifying patients with painful neuropathies., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Painful and disabling musculoskeletal disorders remain prevalent. In rats trained to perform repetitive tasks leading to signs and dysfunction similar to those in humans, we tested whether manual therapy would prevent the development of the pathologies and symptoms. We collected behavioral, electrophysiological, and histological data from control rats, rats that trained for 5 weeks before performing a high-repetition high-force (HRHF) task for 3 weeks untreated, and trained rats that performed the task for 3 weeks while being treated 3x/week using modeled manual therapy (MMT) to the forearm (HRHF + MMT). The MMT included bilateral mobilization, skin rolling, and long axis stretching of the entire upper limb. High-repetition high-force rats showed decreased performance of the operant HRHF task and increased discomfort-related behaviors, starting after training. HRHF + MMT rats showed improved task performance and decreased discomfort-related behaviors compared with untreated HRHF rats. Subsets of rats were assayed for presence or absence of ongoing activity in C neurons and slow Aδ neurons in their median nerves. Neurons from HRHF rats had a heightened proportion of ongoing activity and altered conduction velocities compared with control and MMT-treated rats. Median nerve branches in HRHF rats contained increased numbers of CD68 macrophages and degraded myelin basic protein, and showed increased extraneural collagen deposition, compared with the other groups. We conclude that the performance of the task for 3 weeks leads to increased ongoing activity in nociceptors, in parallel with behavioral and histological signs of neuritis and nerve injury, and that these pathophysiologies are largely prevented by MMT.

Nociceptors are sensory neurons that detect harmful, or potentially harmful, stimuli, and can become sensitized following injury or repetitive stimulation. When sensitized, nociceptors often exhibit activity in the absence of apparent or additional stimulation, called ongoing (or spontaneous) activity (OA). In this report, we provide evidence that OA in nociceptors can be caused by the stimuli typically used to identify and characterize the neuron, which must by definition be noxious and therefore potentially sensitizing. Such OA caused by the experimental methodology can confound interpretation. In our nerve inflammation model, OA can potentially arise from multiple sites, including the lesion site and the receptive field. We provide evidence that the OA rate recorded during these experiments may be related to the site and cause of OA generation. We suggest that there are two types of OA, characterized by their rates. Very slow rates of ongoing activity (<0.2 Hz) are likely to arise from the receptive field and may indicate sensitization during the experiment. Faster rates are likely to arise from the nerve trunk, i.e. the neuritis, or the neuronal cell body. Without appropriate methodological consideration, interpretations of results from such studies of nociceptor function may be methodologically confounded., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Nerves are usually viewed as simple conduits of electrical signals to make muscles move and enable sensation. However, recent data have shown that the axons within nerves are capable of responding to their environment. Nerves have a very specialized anatomy and physiology, and are capable of mediating certain types of pain. This synopsis introduces the reader to these concepts, which can be incorporated into clinical decision-making.

Unlabelled: The present study is an in vivo investigation into the time course of inflammation-induced axonal mechanical sensitivity (AMS) in intact C-fiber axons. After induction of a localized neuritis in the rat sciatic nerve, AMS developed in C-fiber axons at 1 (18.2%) and 4 weeks (11.6%). By 8 weeks, AMS was virtually absent (2.1%). AMS was also tested in intact L5 neurons after L4 spinal nerve transection, which induces a diffuse inflammation within the sciatic nerve. At 1 week, AMS developed in 10% of neurons. No AMS was observed in unoperated animals. The localized neuritis also caused changes in L5 dorsal root conduction velocities (CVs). CVs decreased at 1 week (-7.7%) and 4 weeks (-17.6%) and returned to normal by 8 weeks. L4 transection similarly reduced CVs (-13.7%) of L5 dorsal root axons. There were no significant changes among any groups in the proportion or rate of ongoing activity. These results demonstrate that the axonal changes due to neuritis are not permanent. Therefore, in patients with persistent movement-induced radiating limb pain with few clinically apparent signs of nerve damage, there may be a persisting inflammatory lesion affecting the nerve., Perspective: Nerve inflammation, or neuritis, causes axonal mechanical sensitivity, which is the neural substrate for radiating limb pain induced by movement. This study examined the time course of induced axonal mechanical sensitivity and conduction velocity changes in intact C-fiber axons after nerve inflammation. The results suggest that treatment to reduce nerve inflammation may be beneficial to patients with radiating pain.

We describe a method for evaluating the threshold for cutaneous mechanical sensation in rodents, based on a stimulator that drives a probe against the plantar surface of the foot. The stimulator applies loads that can be either constant or linearly increased. We describe withdrawal responses, including forms of movement that precede foot withdrawals. With constant stimuli, response latency declines in a nonlinear fashion as stimulus magnitude is increased. With ramped stimuli the effect of loading rate is complex, reflecting both the rate of change of the stimulus and the animal's reaction time. We demonstrate the utility of using ramped stimuli in experiments that show that thresholds vary spatially across the foot and experiments that show that intradermal capsaicin injections cause allodynia but not hyperalgesia.

A variety of seemingly diverse pain syndromes are characterized by movement-induced pain radiating in the distribution of a peripheral nerve or nerve root. This could be explained by the induction of ectopic mechanical sensitivity in intact sensory axons. Here we show that inflammation led to mechanical sensitivity of the axons of a subset of mechanically sensitive primary sensory neurons. Dorsal root recordings were made from 194 mechanically sensitive neurons that innervated deep and cutaneous structures and had C, Adelta, and Aalphabeta conduction velocities. No axons of any category were mechanically sensitive in control experiments. However, the axons of neurons innervating deep structures and having C- or Adelta-conduction velocities became mechanically sensitive during the neuritis, and also exhibited an increased incidence of spontaneous discharge. The incidence of mechanical sensitivity followed a distinct time course. In some cases, paw withdrawal thresholds were obtained after neuritis induction. The time course of the resultant hypersensitivity was not directly related to the time course of the axonal mechanical sensitivity. Ectopic axonal mechanical sensitivity could explain some types of radiating, nerve-related pain coexisting with diseases of seemingly diverse etiologies.

Noxious heat may act as an endogenous activator of the ionotropic capsaicin receptor (VR1) and of its recently found homologue VRL1, expressed in rat dorsal root ganglion cells and present along their nerve fibres. We have previously reported that capsaicin induces receptor-mediated and Ca++-dependent calcitonin gene-related peptide (CGRP) release from axons of the isolated rat sciatic nerve. Here we extended the investigation to noxious heat stimulation and the transduction mechanisms involved. Heat stimulation augmented the CGRP release from desheathed sciatic nerves in a log-linear manner with a Q10 of approximately 15 and a threshold between 40 and 42 degrees C. The increases were 1.75-fold at 42 degrees C, 3.8-fold at 45 degrees C and 29.1-fold at 52 degrees C; in Ca++-free solution these heat responses were abolished or reduced by 71 and 92%, respectively. Capsazepine (10 microm) and Ruthenium Red (1 microm) used as capsaicin receptor/channel antagonists did not significantly inhibit the heat-induced release. Pretreatment of the nerves with capsaicin (100 microm for 30 min) caused complete desensitization to 1 microm capsaicin, but a significant heat response remained, indicating that heat sensitivity is not restricted to capsaicin-sensitive fibres. The sciatic nerve axons responded to heat, potassium and capsaicin stimulation with a Ca++-dependent CGRP release. Blockade of the capsaicin receptor/channels had little effect on the heat-induced neuropeptide release. We conclude therefore that other heat-activated ion channels than VR1 and VRL1 in capsaicin-sensitive and -insensitive nerve fibres may cause excitation, axonal Ca++ influx and subsequent CGRP release.

Pressure pain thresholds and responses to painful mechanical stimuli were obtained from 20 subjects with episodic tension-type headaches (TTH). Tender points in the temporalis and trapezius muscles were studied, along with two nontender points, one in the temporalis and one on the Achilles tendon. Two examinations were performed, one during and one without a headache, and results were compared. No significant differences were found in either variable for any tested points. The data demonstrate that the sensitivity level of these points does not differ based on the presence or absence of TTH. This suggests that the muscle sensitivity in TTH is constant. The observation that the sensitivity levels of both tender and nontender points did not vary suggests that the underlying mechanism or effect of TTH is not restricted to tender muscles.

The presence of an intrinsic afferent innervation of nerves and their connective tissues (nervi nervorum) suggests that these neural elements participate in sensation and pathological processes affecting nerves. Primary afferent nociceptors contain and release neuropeptides including calcitonin gene-related peptide, implicated in inflammatory vasodilatation. We sought to evaluate the ability of different peripheral nerve components, in vitro, to release calcitonin gene-related peptide and prostaglandin E2 in response to electrical and noxious chemical stimuli, using sensitive enzyme immunoassays. We observed significant increases in both calcitonin gene-related peptide and prostaglandin E2 in response to a mixture of inflammatory mediators (bradykinin, histamine, and serotonin; 10(-5) M) applied to the intact nerves (+37% and +700%, respectively) and isolated sheaths (35% and 430%, respectively), but not when this mixture was applied to isolated axons. Proximal (antidromic) but not distal (orthodromic) electrical stimulation also evoked a comparable release of calcitonin gene-related peptide (+30%) from intact nerves. These results suggest that nervi nervorum nociceptors participate in neural inflammation. Capsaicin (10(-6) M) elicited a very large release of calcitonin gene-related peptide when applied to either the intact nerve (+400%), isolated sheaths (+500%), or isolated axons (1400%). The latter effect was substantially but not completely blocked by Ruthenium Red and capsazepine, and was completely blocked using a calcium-free bathing solution. The results support the presence of capsaicin receptors in peripheral nerves that can effect calcitonin gene-related peptide release from axons as well as from terminals.