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Radiation-induced fibrosis (RIF) is a common side effect of cancer treatment, but can manifest into a devastating syndrome for which there is no preventive measure or cure. In rats who perform a repetitive work task, who left untreated develop signs and symptoms that resemble repetitive motion disorders in humans, we have shown that manual therapy prevents the development of fibrosis and other key biomarkers. The fibrosis of RIF and repetitive motion disorders has similar biomarkers. In rats, we sought to determine if manual therapy would alter key biomarkers of post-irradiation fibrosis following X-ray irradiation given to the rat forelimb. One limb of rats was given a damaging dose of X-ray irradiation. Some limbs were massaged using a protocol previously described and characterized. Serum inflammatory markers, histological assays of tissue fibrosis and nerve pathology, and electrophysiology for neuropathic discharge were assayed after 8 weeks. We also tested if an experienced therapist could identify the irradiated limb using blinded palpation at the 8 week end-point. While preliminary assays showed robust changes compared to control limbs, the other assays did not show similar pathology. Our therapist could detect each irradiated limb. Serum inflammatory markers were reduced by massage to the irradiated limb. We conclude that blinded palpation is sensitive to detect subtle changes in tissue following irradiation. In contrast to the preliminary studies, the dose of irradiation used was insufficient to induce long-lasting deep fibrosis or nerve degeneration. We suspect that a difference in housing, and thus physical activity, was the plausible reason for this difference.

A case of anteromedial leg pain diagnosed and treated for 10 years as "shin splints" (medial tibial stress syndrome) is described. A history and examination was performed focused on anatomy, biomechanics, and peripheral nerves. Detailed sensory testing was performed in the painful area, and imaging was obtained to confirm the diagnosis. The clinical investigation was consistent with dynamic stenosis of the left L4-5 intervertebral foramen, causing a mixed partial mononeuropathy of the L4 spinal nerve that presented as pain and hypersensitivity in the anteromedial shin. Manual therapy maneuvers intended to open the intervertebral foramen led to resolution of the pain and sensory deficits. After three additional treatments performed within a month, resolution was maintained for >3 years. This case highlights how concepts from preclinical studies, coupled with basic anatomical, neurological, and biomechanical investigations, can be critical for accurate diagnosis and treatment for a case previously considered unresponsive to care., Competing Interests: The author has no disclaimers, competing interests, or sources of support or funding to report in the preparation of this manuscript. The involved patient provided consent for case publication., (© JCCA 2023.)

The effectiveness of manual therapy in reducing the catabolic effects of performing repetitive intensive force tasks on bones has not been reported. We examined if manual therapy could reduce radial bone microstructural declines in adult female Sprague-Dawley rats performing a 12-week high-repetition and high-force task, with or without simultaneous manual therapy to forelimbs. Additional rats were provided 6 weeks of rest after task cessation, with or without manual therapy. The control rats were untreated or received manual therapy for 12 weeks. The untreated TASK rats showed increased catabolic indices in the radius (decreased trabecular bone volume and numbers, increased osteoclasts in these trabeculae, and mid-diaphyseal cortical bone thinning) and increased serum CTX-1, TNF-α, and muscle macrophages. In contrast, the TASK rats receiving manual therapy showed increased radial bone anabolism (increased trabecular bone volume and osteoblast numbers, decreased osteoclast numbers, and increased mid-diaphyseal total area and periosteal perimeter) and increased serum TNF-α and muscle macrophages. Rest, with or without manual therapy, improved the trabecular thickness and mid-diaphyseal cortical bone attributes but not the mineral density. Thus, preventive manual therapy reduced the net radial bone catabolism by increasing osteogenesis, while rest, with or without manual therapy, was less effective.

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.)

Manual therapies have been practiced for centuries, yet little research has been performed to understand their efficacy and almost no animal research has been performed to inform mechanisms of action. The methods of manual therapy practice are quite varied and present a challenge for scientists to model the treatments and perform research using rodents. In this perspective we present a descriptive analysis of the complexity of the treatments, highlighting the role of tissue mechanics and physics. With these complexities in mind, we compare using manual therapy as clinically practiced, to attempts to develop machinery to model or mimic manual therapy. We propose that because of the complexities of manual therapy as practiced, having therapists perform the treatments on research animals just as they would on humans is the most scientific approach. Our results using this approach have supported its practicality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bove, Chapelle, Barrigar and Barbe.)

Background : Repetitive strain injuries caused by repetitive occupational work are difficult to prevent for multiple reasons. Therefore, we examined the effectiveness of manual therapy (MT) with rest to treat the inflammation and fibrosis that develops through the performance of a repetitive task. We hypothesized that this treatment would reduce task-induced sensorimotor declines and neuromuscular inflammation. Methods : Twenty-nine female Sprague-Dawley rats performed a reaching and lever-pulling task for 14weeks. All ceased performing the task at 14weeks. Ten were euthanized at this timepoint (TASK). Nine received manual therapy to their upper extremities while resting 7weeks (MTR); 10 were assigned to rest alone (REST). Ten additional food restricted rats were included that neither performed the task nor received manual therapy (FRC). Results : Confirming previous experiments, TASK rats showed behavioral changes (forepaw mechanical hypersensitivity, reduced grip strength, lowered forelimb/forepaw agility, and noxious cold temperature sensitivity), reduced median nerve conduction velocity (NCV), and pathological tissue changes (myelin degradation, increased median nerve and muscle inflammation, and collagen production). Manual therapy with rest (MTR) ameliorated cold sensitivity seen in REST rats, enhanced muscle interleukin 10 (IL-10) more than in REST rats, lead to improvement in most other measures, compared to TASK rats. REST rats showed improved grip strength, lowered nerve inflammation and degraded myelin, and lowered muscle tumor necrosis factor alpha (TNFα) and collagen I levels, compared to TASK rats, yet maintained lowered forelimb/forepaw agility and NCV, and increased neural fibrosis. Conclusion : In our model of repetitive motion disorder, manual therapy during rest had modest effects on behavioral, histological, and physiological measures, compared to rest alone. These findings stand in contrast to the robust preventive effects of manual therapy in this same model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Barbe, Panibatla, Harris, Amin, Dorotan, Cruz and Bove.)

Background: We examined the effectiveness of a manual therapy consisting of forearm skin rolling, muscle mobilization, and upper extremity traction as a preventive treatment for rats performing an intensive lever-pulling task. We hypothesized that this treatment would reduce task-induced neuromuscular and tendon inflammation, fibrosis, and sensorimotor declines., Methods: Sprague-Dawley rats performed a reaching and lever pulling task for a food reward, 2 h/day, 3 days/week, for 12 weeks, while simultaneously receiving the manual therapy treatment 3 times per week for 12 weeks to either the task-involved upper extremities (TASK-Tx), or the lower extremities as an active control group (TASK-Ac). Results were compared to similarly treated control rats (C-Tx and C-Ac)., Results: Median nerves and forearm flexor muscles and tendons of TASK-Ac rats showed higher numbers of inflammatory CD68+ and fibrogenic CD206+ macrophages, particularly in epineurium, endomysium and epitendons than TASK-Tx rats. CD68+ and CD206+ macrophages numbers in TASK-Tx rats were comparable to the non-task control groups. TASK-Ac rats had more extraneural fibrosis in median nerves, pro-collagen type I levels and immunoexpression in flexor digitorum muscles, and fibrogenic changes in flexor digitorum epitendons, than TASK-Tx rats (which showed comparable responses as control groups). TASK-Ac rats showed cold temperature, lower reflexive grip strength, and task avoidance, responses not seen in TASK-Tx rats (which showed comparable responses as the control groups)., Conclusions: Manual therapy of forelimbs involved in performing the reaching and grasping task prevented the development of inflammatory and fibrogenic changes in forearm nerves, muscle, and tendons, and sensorimotor declines.

Radiating pain is a significant feature of chronic musculoskeletal pain conditions such as radiculopathies, repetitive motion disorders and whiplash associated disorders. It is reported to be caused by the development of mechanically-sensitive ectopic receptive fields along intact nociceptor axons at sites of peripheral neuroinflammation (neuritis). Since inflammation disrupts axonal transport, we have hypothesised that anterogradely-transported mechanically sensitive ion channels accumulate at the site of disruption, which leads to axonal mechanical sensitivity (AMS). In this study, we have characterised the mechanical properties of the ectopic axonal receptive fields in the rat and have examined the contribution of mechanically sensitive ion channels to the development of AMS following neuritis and vinblastine-induced axonal transport disruption. In both models, there was a positive force-discharge relationship and mechanical thresholds were low (∼9 mN/mm 2 ). All responses were attenuated by Ruthenium Red and FM1-43, which block mechanically sensitive ion channels. In both models, the transport of TRPV1 and TRPA1 was disrupted, and intraneural injection of agonists of these channels caused responses in neurons with AMS following neuritis but not vinblastine treatment. In summary, these data support a role for mechanically sensitive ion channels in the development of AMS., (Copyright © 2019 IBRO. Published by Elsevier Ltd. 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.

Local nerve inflammation (neuritis) leads to ongoing activity and axonal mechanical sensitivity (AMS) along intact nociceptor axons and disrupts axonal transport. This phenomenon forms the most feasible cause of radiating pain, such as sciatica. We have previously shown that axonal transport disruption without inflammation or degeneration also leads to AMS but does not cause ongoing activity at the time point when AMS occurs, despite causing cutaneous hypersensitivity. However, there have been no systematic studies of ongoing activity during neuritis or noninflammatory axonal transport disruption. In this study, we present the time course of ongoing activity from primary sensory neurons following neuritis and vinblastine-induced axonal transport disruption. Whereas 24% of C/slow Aδ-fiber neurons had ongoing activity during neuritis, few (<10%) A- and C-fiber neurons showed ongoing activity 1-15 days following vinblastine treatment. In contrast, AMS increased transiently at the vinblastine treatment site, peaking on days 4-5 (28% of C/slow Aδ-fiber neurons) and resolved by day 15. Conduction velocities were slowed in all groups. In summary, the disruption of axonal transport without inflammation does not lead to ongoing activity in sensory neurons, including nociceptors, but does cause a rapid and transient development of AMS. Because it is proposed that AMS underlies mechanically induced radiating pain, and a transient disruption of axonal transport (as previously reported) leads to transient AMS, it follows that processes that disrupt axonal transport, such as neuritis, must persist to maintain AMS and the associated symptoms. NEW & NOTEWORTHY Many patients with radiating pain lack signs of nerve injury on clinical examination but may have neuritis, which disrupts axonal transport. We have shown that axonal transport disruption does not induce ongoing activity in primary sensory neurons but does cause transient axonal mechanical sensitivity. The present data complete a profile of key axonal sensitivities following axonal transport disruption. Collectively, this profile supports that an active peripheral process is necessary for maintained axonal sensitivities.

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.)

Postoperative adhesions are pathological attachments that develop between abdominopelvic structures following surgery. Considered unavoidable and ubiquitous, postoperative adhesions lead to bowel obstructions, infertility, pain, and reoperations. As such, they represent a substantial health care challenge. Despite over a century of research, no preventive treatment exists. We hypothesized that postoperative adhesions develop from a lack of movement of the abdominopelvic organs in the immediate postoperative period while rendered immobile by surgery and opiates, and tested whether manual therapy would prevent their development. In a modified rat cecal abrasion model, rats were allocated to receive treatment with manual therapy or not, and their resulting adhesions were quantified. We also characterized macrophage phenotype. In separate experiments we tested the safety of the treatment on a strictureplasty model, and also the efficacy of the treatment following adhesiolysis. We show that the treatment led to reduced frequency and size of cohesive adhesions, but not other types of adhesions, such as those involving intraperitoneal fatty structures. This effect was associated with a delay in the appearance of trophic macrophages. The treatment did not inhibit healing or induce undesirable complications following strictureplasty. Our results support that that maintained movements of damaged structures in the immediate postoperative period has potential to act as an effective preventive for attenuating cohesive postoperative adhesion development. Our findings lay the groundwork for further research, including mechanical and pharmacologic approaches to maintain movements during healing.

Purpose/Aim: Postoperative adhesions remain an undesirable and commonly symptomatic side effect of abdominopelvic surgeries. Animal models of postoperative adhesions typically yield heterogeneous adhesions throughout the abdominal cavity and are not easily quantified. Here we present a novel method of postoperative adhesion assessment and report its reliability and measurement error., Materials and Methods: A model of cecal abrasion with partial sidewall attachment was performed on female rats. After 1, 2, 4, or 7 days of recovery, the rats were euthanized and their abdominopelvic cavities were systematically evaluated for postoperative adhesions. The necropsy was recorded through the surgical microscope. Four raters were trained to use a ballot to capture key factors of the adhesions as they viewed the recordings. Their ratings were compared for measurement error and reliability (using Bland-Altman plots and intraclass correlation coefficients, respectively) and for the ability to discriminate differences in experimental groups. A subset of the data was analyzed to determine practical utility., Results: The rating system was shown to have low measurement error and high inter-rater reliability for all parameters measured. Applied practically, the system was able to discriminate groups in a manner that was expected., Conclusions: We have developed and validated a rating system for postoperative adhesions and shown that it can detect group differences. This method can be used to quantify postoperative adhesions in rodent models.

Endometriosis is a prevalent female health disorder that often leads to back pain and radiating leg pain. Patients with such pain often seek care from multiple health care professionals, including manual therapists. We hypothesized that endometrioma can induce nerve inflammation thus the radiating leg pain that often accompanies endometriosis. To model sciatic endometriosis in female Wistar rats, a section of uterine horn was autotransplanted to the sciatic nerve. Uterus sections with the endometrium removed and autotransplanted to the sciatic nerve served as controls. After 1, 3, and 15 months the nerves were harvested and processed for immune cell presence and for neural elements. Control nerves were harvested after 4 months. All autotransplants survived, resulting in a fusion of the uterus sections to the nerves. Macroscopically, turgid cysts apposed to the nerves characterized the complexes. Microscopically, the complexes contained recruited macrophages, indicating persistent inflammation, and were innervated by small diameter axons. Only 1 of 8 control rats developed a small cyst, presumably due to residual endometrium. The persistent immune response and innervation suggest the nerve-uterus complexes as sources of inflammation and persistent neural discharge, and thus pain. This model could shed light upon the radiating leg pain that often accompanies endometriosis. Manual therapists should be aware of the possibility of endometriosis causing symptoms and examination findings that mimic musculoskeletal etiologies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Rationale  Knowledge of the relationship of the dorsal scapular artery (DSA) with the brachial plexus is limited. Objective  We report a case of a variant DSA path, and revisit DSA origins and under-investigated relationship with the plexus in cadavers. Methods  The DSA was examined in a male patient and 106 cadavers. Results  In the case, we observed an unusual DSA compressing the lower plexus trunk, that resulted in intermittent radiating pain and paresthesia. In the cadavers, the DSA originated most commonly from the subclavian artery (71%), with 35% from the thyrocervical trunk. Nine sides of eight cadavers (seven females) had two DSA branches per side, with one branch from each origin. The most typical DSA path was a subclavian artery origin before passing between upper and middle brachial plexus trunks (40% of DSAs), versus between middle and lower trunks (23%), or inferior (4%) or superior to the plexus (1%). Following a thyrocervical trunk origin, the DSA passed most frequently superior to the plexus (23%), versus between middle and lower trunks (6%) or upper and middle trunks (4%). Bilateral symmetry in origin and path through the brachial plexus was observed in 13 of 35 females (37%) and 6 of 17 males (35%), with the most common bilateral finding of a subclavian artery origin and a path between upper and middle trunks (17%). Conclusion  Variability in the relationship between DSA and trunks of the brachial plexus has surgical and clinical implications, such as diagnosis of thoracic outlet syndrome.

Key clinical features of carpal tunnel syndrome and other types of cumulative trauma disorders of the hand and wrist include pain and functional disabilities. Mechanistic details remain under investigation but may involve tissue inflammation and/or fibrosis. We examined the effectiveness of modeled manual therapy (MMT) as a treatment for sensorimotor behavior declines and increased fibrogenic processes occurring in forearm tissues of rats performing a high repetition high force (HRHF) reaching and grasping task for 12 weeks. Young adult, female rats were examined: food restricted control rats (FRC, n=12); rats that were trained for 6 weeks before performing the HRHF task for 12 weeks with no treatment (HRHF-CON, n=11); and HRHF task rats received modeled manual therapy (HRHF-MMT, n=5) for 5 days/week for the duration of the 12-week of task. Rats receiving the MMT expressed fewer discomfort-related behaviors, and performed progressively better in the HRHF task. Grip strength, while decreased after training, improved following MMT. Fibrotic nerve and connective tissue changes (increased collagen and TGF-β1 deposition) present in 12-week HRHF-CON rats were significantly decreased in 12-week HRHF-MMT rats. These observations support the investigation of manual therapy as a preventative for repetitive motion disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: Many factors alter gastrointestinal transit. Animal models are useful for preclinical studies of gastrointestinal transit, but terminal methods do not allow later study, and stressful assessment methods will likely alter the transit of the animal. To overcome these factors, we developed a new method to assay rat total gastrointestinal transit., Methods: Standard plastic cages with their bottoms cut off were placed on wire mesh floors. Custom apparatuses were built to contain fecal pellets as they fell through the floors. Webcams connected to a computer running a security program were placed to image the pellets at regular intervals. Custom food was obtained with and without blue pigment. After habituating to the cages and the non-pigmented food, the pigmented food was administered. The duration to the appearance of the first pigmented pellet was determined by reviewing the photographs. This duration represents the complete gastrointestinal behavior, including feeding. We compared 24-hour fecal pellet counts using images to counts by visual inspection, and also made hourly counts. After establishing baseline transit times and hourly fecal pellet discharge, rats were given buprenorphine, known to alter gastrointestinal transit. Transit times and hourly discharge were obtained again and compared to the baselines., Results: The methods were successful in determining transit times. Baseline measures were consistent between three groups of 8 rats. Visual and image-based counts were highly correlated. Transit times and hourly pellet discharge were reduced by buprenorphine., Discussion: The described method offers a relatively simple, inexpensive, and non-invasive means to measure rat gastrointestinal behavior. The method has potential for any study where altered total gastrointestinal transit is an experimental concern., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Key clinical features of cumulative trauma disorders include pain, muscle weakness, and tissue fibrosis, although the etiology is still under investigation. Here, we characterized the temporal pattern of altered sensorimotor behaviors and inflammatory and fibrogenic processes occurring in forearm muscles and serum of young adult, female rats performing an operant, high repetition high force (HRHF) reaching and grasping task for 6, 12, or 18 weeks. Palmar mechanical sensitivity, cold temperature avoidance and spontaneous behavioral changes increased, while grip strength declined, in 18-week HRHF rats, compared to controls. Flexor digitorum muscles had increased MCP-1 levels after training and increased TNFalpha in 6-week HRHF rats. Serum had increased IL-1beta, IL-10 and IP-10 after training. Yet both muscle and serum inflammation resolved by week 18. In contrast, IFNγ increased at week 18 in both muscle and serum. Given the anti-fibrotic role of IFNγ, and to identify a mechanism for the continued grip strength losses and behavioral sensitivities, we evaluated the fibrogenic proteins CCN2, collagen type I and TGFB1, as well as the nociceptive/fibrogenic peptide substance P. Each increased in and around flexor digitorum muscles and extracellular matrix in the mid-forearm, and in nerves of the forepaw at 18 weeks. CCN2 was also increased in serum at week 18. At a time when inflammation had subsided, increases in fibrogenic proteins correlated with sensorimotor declines. Thus, muscle and nerve fibrosis may be critical components of chronic work-related musculoskeletal disorders. CCN2 and substance P may serve as potential targets for therapeutic intervention, and CCN2 as a serum biomarker of fibrosis progression.

The theory of myofascial pain syndrome (MPS) caused by trigger points (TrPs) seeks to explain the phenomena of muscle pain and tenderness in the absence of evidence for local nociception. Although it lacks external validity, many practitioners have uncritically accepted the diagnosis of MPS and its system of treatment. Furthermore, rheumatologists have implicated TrPs in the pathogenesis of chronic widespread pain (FM syndrome). We have critically examined the evidence for the existence of myofascial TrPs as putative pathological entities and for the vicious cycles that are said to maintain them. We find that both are inventions that have no scientific basis, whether from experimental approaches that interrogate the suspect tissue or empirical approaches that assess the outcome of treatments predicated on presumed pathology. Therefore, the theory of MPS caused by TrPs has been refuted. This is not to deny the existence of the clinical phenomena themselves, for which scientifically sound and logically plausible explanations based on known neurophysiological phenomena can be advanced., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Unlabelled: Studies of peripheral nerve inflammation (neuritis) suggest that some symptoms of neuropathic pain can be generated from inflamed but otherwise uninjured axons. We have previously inferred a role for inflammation-induced axonal transport disruption in the underlying mechanisms. In the present study, we have investigated the development of sensory hypersensitivities following vinblastine-induced axonal transport disruption. Similar to neuritis, locally applied .1 mM vinblastine caused the rapid development of mechanical hypersensitivity within the first week postsurgery. The same animals did not develop heat hypersensitivity. Because aberrant firing from primary sensory neurons is considered necessary to drive spinal mechanisms that lead to hypersensitivities, the levels of ongoing activity and axonal mechanical sensitivity were examined. Recordings from A- and C-fiber neurons did not reveal differences in the levels of ongoing activity between vinblastine-treated (<5.8%) and saline-treated control animals (<4.6%). However, 28% of C-fiber axons were mechanically sensitive at the vinblastine treatment site. Using kinesin immunohistochemistry, we confirmed a reduction of anterograde axonal transport in vinblastine-treated and neuritis animals. In summary, this study has revealed an alternative pain model, which may be relevant to conditions that are not accompanied by frank nerve injury., Perspective: In this study, we expand our previous reports and demonstrate that focal reduced axonal transport causes distal mechanical hypersensitivity considered consistent with neuropathic pain but in the absence of nerve injury. These findings may inform pain conditions that have a neural inflammatory component., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: Abdominal surgery invariably causes a temporary reduction of normal intestinal motility, called postoperative ileus. Postoperative ileus extends hospital stays, increases the costs of hospitalization, and may contribute to the formation of postoperative adhesions. We designed experiments to determine if visceral massage affects postoperative ileus in a rat model., Material and Methods: Forty female Long Evans rats were assigned to 4 groups in a 2 (surgery) × 2 (treatment) factorial design. Twenty rats were subjected to a small intestinal manipulation designed to emulate "running of the bowel." Transabdominal massage was performed upon 10 operated and 10 control rats in the first 12 h following surgery. Ileus was assayed after 24 h using fecal pellet discharge and gastrointestinal transit. Intraperitoneal inflammation was assayed using total intraperitoneal protein and inflammatory cell concentrations., Results: The surgery consistently caused ileus. Compared to the operated group with no treatment, the operated with treatment group showed increased gastrointestinal transit and reduced time to first fecal pellet discharge. Similar group comparisons revealed that the treatment decreased total intraperitoneal protein and numbers of intraperitoneal inflammatory cells., Conclusions: In this rat model, visceral massage reduced experimental postoperative ileus. The data suggest that the effect was through the attenuation of inflammation. A similar study could be designed and performed in a hospital setting to assess the potential role of visceral massage as part of the integrated care for postoperative ileus., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Peritoneal adhesions are almost ubiquitous following surgery. Peritoneal adhesions can lead to bowel obstruction, digestive problems, infertility, and pain, resulting in many hospital readmissions. Many approaches have been used to prevent or treat adhesions, but none offer reliable results. A method that consistently prevented or treated adhesions would benefit many patients. We hypothesized that an anatomically-based visceral mobilization, designed to promote normal mobility of the abdominal contents, could manually lyse and prevent surgically-induced adhesions., Material and Methods: Cecal and abdominal wall abrasion was used to induce adhesions in 3 groups of 10 rats (Control, Lysis, and Preventive). All rats were evaluated 7 days following surgery. On postoperative day 7, unsedated rats in the Lysis group were treated using visceral mobilization, consisting of digital palpation, efforts to manually lyse restrictions, and mobilization of their abdominal walls and viscera. This was followed by immediate post-mortem adhesion evaluation. The rats in the Preventive group were treated daily in a similar fashion, starting the day after surgery. Adhesions in the Control rats were evaluated 7 days after surgery without any visceral mobilization., Results: The therapist could palpate adhesions between the cecum and other viscera or the abdominal wall. Adhesion severity and number of adhesions were significantly lower in the Preventive group compared to other groups. In the Lysis and Preventive groups there were clear signs of disrupted adhesions., Conclusions: These initial observations support visceral mobilization may have a role in the prevention and treatment of post-operative adhesions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Radiating leg pain is a common symptom presenting in manual therapy practices. Although this symptom has been reported as a complication of endometriosis, its prevalence and characteristics have not been studied. We surveyed members of a national endometriosis support group with endometriosis using a self-administered, mailed questionnaire. The main outcome measures were the prevalence and characteristics of leg pain. Of 94 respondents, leg pain was reported by 48 women (51%), and was bilateral in 59% of these symptomatic women. The likelihood of experiencing leg pain was related to weight gain since age 18, age, and height. The most common treatments tried included exercise, over-the-counter medications, and massage therapy, all with variable results. These data support leg pain as a prevalent complication of endometriosis, and that the disease may affect multiple peripheral nerves. Manual therapists should remain aware to this possible etiology for radiating pain., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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.)

Early forms of complex regional pain syndromes (CRPS) are characterized by severe pain and autonomic dysfunction in a limb, both of which seem out of proportion to the inciting event. While often caused by obvious nerve injury, the syndromes also occur following relatively trivial trauma. Persistent inflammation has been implicated in the etiology of CRPS. We hypothesized that inflammation of a nerve proximal to the symptoms could lead to neural changes consistent with clinical CRPS. Using a rat model of neuritis, the activity of sensory and autonomic neurons was recorded distal to the inflamed site using single fiber electrophysiological methods. In normal rats, no sensory neurons had ongoing activity. The discharge rate of sympathetic postganglionic neurons was 2.26+/-1.33 Hz (mean+/-SD). However, in rats with inflamed nerves, 27% of slowly conducting neurons had ongoing activity after 3-4 days, and 50% had such activity after 7-8 days. Other sensory neurons did not exhibit ongoing activity. Sympathetic postganglionic neurons had a significantly slower ongoing discharge rate during inflammation (1.96+/-1.19 Hz after 3-4 days, 1.48+/-1.23 Hz after 7-8 days). Additionally, none of the sympathetic axons in any group were mechanically sensitive. These findings support that focal nerve inflammation is sufficient to cause neuronal discharge changes that are consistent with clinical findings in early CRPS. Furthermore, the lack of axonal mechanical sensitivity in sympathetic axons rules out channels expressed in these neurons as possible mechano-electrical transducers.

Immune-mediated nerve inflammation is involved in many painful states in humans, and causes axonal and behavioral changes in rats. While models of nerve inflammation have been characterized using electrophysiological and behavioral methods, the presence of immune cells has not been fully assessed. We inflamed rat sciatic nerves using complete Freund's adjuvant and quantified the presence of ED-1 macrophages and TCR-alphabeta T-cells for up to 12 weeks. We report that these immune cells are prominent extraneurally up to 12 weeks following the induction of inflammation. This observation does not easily correlate with inflammation-induced axonal mechanical sensitivity, which peaks within 1 week and is resolved after 8 weeks.

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.

The following commentary discusses the concept of a chiropractic healer. A model is proposed to describe the elements of a successful chiropractic healer that includes knowledge and manual skill, specific interpersonal skills and attributes, and the attainment of a healing presence. The achievement of a healing presence, which represents the highest level of presence, is emphasized along with effective doctor-patient communication.

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.

Objective: This case report describes and discusses a patient with a pheochromocytoma who presented to a chiropractic office with low back pain., Clinical Features: The patient is a 51-year-old woman who was self-referred to our chiropractic service with low back pain that appeared to be musculoskeletal in nature. Four days after chiropractic consultation, she collapsed in cardiogenic shock with signs of congestive heart failure, left ventricular dysfunction, and hypotension. Computed tomographic image of the abdomen revealed a right-sided adrenal mass that was confirmed via laboratory analysis to be a pheochromocytoma., Intervention and Outcome: The patient underwent laparoscopic adrenalectomy and made a full recovery. Her initial back symptoms resolved with tumor excision., Conclusion: Pheochromocytomas are rare catecholamine-producing tumors of the adrenal glands that can mimic musculoskeletal conditions such as low back pain. Chiropractic physicians should be aware of the various clinical presentations and, when pheochromocytoma is suspected, make prompt referral to medical providers for diagnostic evaluation and treatment.

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.

Recent evidence suggests that substance P (SP) is up-regulated in primary sensory neurons following axotomy and that this change occurs in larger neurons that do not usually produce SP. If this is so, then the up-regulation may allow normally neighboring, uninjured, and nonnociceptive dorsal root ganglion (DRG) neurons to become effective in activating pain pathways. By using immunohistochemistry, we performed a unilateral L5 spinal nerve transection on male Wistar rats and measured SP expression in ipsilateral L4 and L5 DRGs and contralateral L5 DRGs at 1-14 days postoperatively (dpo) and in control and sham-operated rats. In normal and sham-operated DRGs, SP was detectable almost exclusively in small neurons (< or =800 microm2). After surgery, the mean size of SP-positive neurons from the axotomized L5 ganglia was greater at 2, 4, 7, and 14 dpo. Among large neurons (>800 microm2) from the axotomized L5, the percentage of SP-positive neurons increased at 2, 4, 7, and 14 dpo. Among small neurons from the axotomized L5, the percentage of SP-positive neurons was increased at 1 and 3 dpo but was decreased at 7 and 14 dpo. Thus, SP expression is affected by axonal damage, and the time course of the expression is different between large and small DRG neurons. These data support a role for SP-producing, large DRG neurons in persistent sensory changes resulting from nerve injury., (Copyright 2006 Wiley-Liss, Inc.)

Background: Lumbar pathologies may cause the perception of leg pain, but the character of this pain has not been described. Diagnosis is often based on dermatomal charts, but observations reveal that the pain is not typically perceived on the skin., Objective: To document the incidence of superficial versus deep pain localization among patients with lumbar radicular pain., Methods: Twenty-five patients with lower limb radicular pain were questioned to determine the specific localization of their pain. The investigator categorized the pain location into general areas (eg, posterior thigh or anterior leg). Patients were asked if their pain was perceived as being on the skin or deep, as a forced choice question. These data were gathered in 2 conditions: at rest (spontaneous pain) and during a straight leg raise test (mechanically evoked pain). Data were recorded using a standardized form for later analysis., Results: In all cases, symptoms were reported to be in deep structures. Pain was typically reported at sites correlated with multiple spinal levels., Conclusion: Because radicular pain symptoms are perceived in deep structures rather than on the skin, the diagnostic value of dermatomal charts is questioned. Clinicians are advised to be specific when questioning patients with radicular pain symptoms and to refer to myotomal and sclerotomal charts when making diagnoses.

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.

Hypersensitivity of the foot produced by a number of sciatic mononeuropathies was assessed and compared. A new tool was used, the strain-gauge algometer, that delivers a noxious stimulus and gives a direct measurement of the force for paw withdrawal. In addition, we report observations of another alteration of the flexion reflex, persistent hindlimb flexion. The mean mechanical threshold for naive rats was 5.9 +/- 0.97 centinewton (standard deviation). A superficial surgical procedure had no effect on mechanical sensitivity. Sham surgeries and a surgery in which a silicone pellet was glued to the sciatic nerve produced moderate increases in mechanical sensitivity. Interventions that produced the greatest reductions in thresholds were carrageenan neuritis, complete Freund's adjuvant neuritis, and the chronic constriction injury (CCI) model. Mechanical thresholds returned to baseline in 2 weeks in all groups. Neuropathic behaviors (licking and holding the paw after the stimulus) were observed more frequently in the CCI group. Persistent hindlimb flexion was only observed in the CCI group. The results support that midaxonal inflammation is sufficient to induce hyperalgesia. The strain-gauge algometer proved to be efficient and reliable, and calculations support that used as described in this report one can demonstrate changes in paw withdrawal thresholds as small as 15%.

The properties of three types of indentation stimulators: filament indenters, a spring gauge indenter, and an electromechanical stimulator, were evaluated by actuating each device against a 3-direction load cell. The on-axis loads produced by filament indenters were independent of the degree of buckling. The off-axis loads produced by a filament increased with the degree of buckling of the filament, and had magnitudes that were up to 25% of the on-axis load. Repeated applications of a filament produced loads whose magnitudes were very consistent. Offsetting the handle of a filament indenter altered the magnitude and the direction of the off-axis load. Because these factors were poorly controlled in hand held trials, off-axis loads were more variable in hand held trials. The spring gauge stimulator was, when hand held, very susceptible to creating large off-axis loads. When the off-axis loads were large, the spring gauge indicator underestimated the true on-axis loads. The electromechanical stimulator produced loads with a very high degree of consistency and could be arranged so that it produced very small off-axis loads.

After injuries to the musculoskeletal system, peripheral nerve axons are exposed to numerous inflammatory mediators, including tumor necrosis factor-alpha (TNF). Exposure of sensory axons to TNF can cause behavioral hypersensitivity in the peripheral innervation territory of the affected axons. The hypothesis that TNF activates nociceptor axons was tested by using teased fiber techniques in the rat. Recordings were made of single nociceptors innervating both deep and cutaneous receptive fields supplied by the sciatic nerve. The axons proximal to the receptive field were exposed to ascending concentrations of TNF (0.01 to 1 ng/mL). In 21% of cutaneous and 9% of deep neurons, TNF rapidly evoked a transient response. There was no difference between deep and cutaneous nociceptors in the incidence of TNF responses. The majority of neurons responded to TNF injected into their receptive fields. Our data support that TNF can induce ectopic electrogenesis in a minority of nociceptor axons that innervate both deep and cutaneous tissues. This activity may correlate to the human perception of radiating pain that often accompanies neuritis.

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.

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.

We made recordings from filaments of guinea pig nasociliary nerve to study response properties of afferent axons innervating the anterior superior sagittal sinus and surrounding dura mater. We analyzed 38 units in 14 experiments. Units were initially located with the use of mechanical stimuli, and were then characterized by their conduction velocity and sensitivities to mechanical, thermal, and chemical stimuli. Single-unit recordings revealed innervation of dura and superior sagittal sinus by slowly conducting axons, mostly in the unmyelinated range. The receptive fields were 1-30 mm2, and typically had one to three punctate spots of highest sensitivity. All units tested responded to topical application of chemical agents. Ninety-seven percent of units responded to 10(-5) M capsaicin, 79% responded to a mixture of inflammatory mediators, and 37% responded to an acidic buffer (pH 5). These data underline the importance of chemical sensitivity in intracranial sensation. Heat and cold stimuli evoked responses in 56 and 41% of units tested, respectively. Although the response patterns during heating were typical of polymodal nociceptors innervating other tissues, the thresholds were lower than for other tissues (32.3-42 degrees C). Cooling led to a phasic discharge, with thresholds between 25 and 32 degrees C. Although units had different combinations of responses to mechanical, chemical, and thermal stimuli, when grouped by their sensitivities the groups did not differ regarding mechanical thresholds or presence of ongoing activity. This suggests that meningeal primary afferents are relatively homogeneous. Sensitivities of these units are in general consistent with nociceptors, although the thermal thresholds differ. These data provide the first detailed report of response properties of intracranial primary afferent units, likely to be involved in transmission of nociception and possibly mediation of intracranial pain.