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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.

We have previously shown that nerve inflammation (neuritis) and transient vinblastine application lead to axonal mechanical sensitivity in nociceptors innervating deep structures. We also have shown that these treatments reduce axonal transport and have proposed that this leads to functional accumulation of mechanically sensitive channels in the affected part of the axons. Though informing the etiology of mechanically induced pain, axonal mechanical sensitivity does not address the common report of ongoing radiating pain during neuritis, which could be secondary to the provocation of axonal chemical sensitivity. We proposed that neuritis and vinblastine application would induce sensitivities to noxious chemicals and that the number of chemo-sensitive channels would be increased at the affected site. In adult female rats, nerves were either untreated or treated with complete Freund's adjuvant (to induce neuritis) or vinblastine. After 3-7 days, dorsal root teased fiber recordings were taken from group IV neurons with axons within the sciatic nerve. Sciatic nerves were injected intraneurally with a combination of noxious inflammatory chemicals. Whereas no normal sciatic axons responded to this stimulus, 80% and 38% of axons responded in the neuritis and vinblastine groups, respectively. In separate experiments, sciatic nerves were partially ligated and treated with complete Freund's adjuvant or vinblastine (with controls), and after 3-5 days were immunolabeled for the histamine H 3 receptor. The results support that both neuritis and vinblastine treatment reduce transport of the histamine H 3 receptor. The finding that nociceptor axons can develop ectopic chemical sensitivity is consistent with ongoing radiating pain due to nerve inflammation. NEW & NOTEWORTHY Many patients suffer ongoing pain with no local pathology or apparent nerve injury. We show that nerve inflammation and transient application of vinblastine induce sensitivity of group IV nociceptor axons to a mixture of endogenous inflammatory chemicals. We also show that the same conditions reduce the axonal transport of the histamine H 3 receptor. The results provide a mechanism for ongoing nociception from focal nerve inflammation or pressure without overt nerve damage., (Copyright © 2017 the American Physiological Society.)

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.

Peripheral nerve inflammation can cause axons conducting through the inflamed site to become mechanically sensitive. Axonal mechanical sensitivity (AMS) of intact axons may explain symptoms in a diverse number of conditions characterized by radiating pain evoked by movements of the affected nerve. Because nerve inflammation also disrupts axoplasmic transport, we hypothesized that the disruption of axoplasmic transport by nerve inflammation could cause the cellular components responsible for mechanical transduction to accumulate and become inserted at the inflamed site, causing AMS. This was tested by examining AMS in C-fibre nociceptors following the application of axoplasmic transport blockers (colchicine and vinblastine) to the sciatic nerve. Both 10 mm colchicine and 0.1 mm vinblastine caused AMS to develop in 30.6% and 33.3% of intact axons, respectively (P < 0.05 compared to sham treatment). Since high doses of colchicine (> 50 mm) can damage axons, and inflammation is involved in the removal of axonal debris, experiments were performed to assess conduction across the treatment site as well as signs of inflammation. Results indicated minimal axonal loss (95% of A- and C-fibres conducting), consistent with the normal microscopic appearance of the colchicine treatment site and absence of ED1-positive (recruited) macrophages. In a separate series of experiments, the block of axoplasmic transport proximal to a localized neuritis significantly reduced inflammation-induced AMS (15.6% compared to 55.6%; P < 0.05), further supporting that the components necessary for AMS are moved by anterograde transport. In summary, nerve inflammation that causes the disruption of axoplasmic transport in patients with painful conditions may result in the accumulation and insertion of mechanosensitive elements at the inflamed site.

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.

1. We made recordings from rat dorsal root filaments to study unmyelinated afferent units (conduction velocity < or = 1.5 m/s) associated with deep paraspinal tissues of the dorsal sacrum and proximal tail. Data from 57 unmyelinated units were analyzed in 47 experiments. Receptive fields were identified in intact animals and then surgically isolated using microdissection. Units were characterized using mechanical, noxious chemical, and thermal stimuli. 2. These recordings revealed innervation of the nerve sheaths and surrounding connective tissue, muscles, tendons, and tissue apposed to the undersurface of the skin. No units were found with receptive fields directly on joint capsular tissue. The receptive fields of the units were often multiple and located in more than one tissue; 31 of 57 units showed convergence from different tissues. 3. The units with receptive fields on neurovascular bundles shared sensitivities with other deep tissue units described in this and other reports. These units may have clinical importance in pain due to peripheral neuropathies. 4. The units initially responded to strong mechanical stimulation of the intact animal and often to noxious stretch of the tail. Once surgically isolated, an individual unit's threshold to mechanical stimuli appeared lower. 5. Capsaicin (0.001%-0.1%) elicited responses in 81% (17 of 21) of the units tested. Bradykinin (20 micrograms/ml) elicited responses in 45% (10 of 22) of the units tested. Noxious cold (4-10 degrees C) and hot (55 degrees C) stimulation elicited discharges from 33% (5 of 15) and 25% (5 of 20) of the units tested, respectively. 6. The unmyelinated units had similar mechanical, chemical, and thermal sensitivities. These similarities and the observed convergence only allowed separation of units by the tissue in which the ending was found, and did not allow further classification. 7. The prevalence of background discharge suggested that many units were sensitized during the experiments. 8. The sensitivities of these paraspinal units were similar to those reported for other tissues. Because of the anatomic similarity of the paraspinal tissues of the proximal tail and the lumbar spine, the conclusions of the present study can be related to the lumbar spine. These afferent units are thought to participate in nociception from the deep paraspinal tissues.

The intrinsic innervation of rat sciatic nerve sheaths was studied by means of immunohistochemical labeling for calcitonin gene-related peptide (CGRP) and peripherin. CGRP immunoreactivity (CGRP-IR) and peripherin immunoreactivity (peripherin-IR) were found in fine nerve fibers independent of nerve sheath vasculature. These findings suggest that a subset of the nervi nervorum may have nociceptive functions, and that this subset is distinct from nerve fibers that innervate the blood vessels of the nerve sheaths.