Radiolucent cerclage for humerus fractures: beware of radial nerve injury-a case report.

A 73-year-old woman was referred to a National Centre for Peripheral Nerve Injury with a post-operative left radial nerve degenerative lesion following open reduction and internal fixation of a proximal third humerus fracture using radiolucent Arthrex FiberTape® Cerclage as an adjunct to plating to improve stability. Intra-operative photographs illustrate compression of the radial nerve under the cerclage construct. Use of radiolucent cerclage for humerus fractures is increasing with modern systems capable of withstanding an ultimate load of 4300 N. We highlight the risk of debilitating neurological injury when not deployed safely and describe anatomical high-risk zones for injury. We emphasize the impact of delay in diagnosis and treatment.

An assessment of co-contraction in reinnervated muscle.

Aim: To investigate co-contraction in reinnervated elbow flexor muscles following a nerve transfer. Materials & methods: 12 brachial plexus injury patients who received a nerve transfer to reanimate elbow flexion were included in this study. Surface electromyography (EMG) recordings were used to quantify co-contraction during sustained and repeated isometric contractions of reinnervated and contralateral uninjured elbow flexor muscles. Reuslts: For the first time, this study reveals reinnervated muscles demonstrated a trend toward higher co-contraction ratios when compared with uninjured muscle and this is correlated with an earlier onset of muscle fatigability. Conclusion: Measurements of co-contraction should be considered within muscular function assessments to help drive improvements in motor recovery therapies.

Virtual Reality combined with Robotic facilitated movements for pain management and sensory stimulation of the upper limb following a Brachial Plexus injury: A case study.

Brachial Plexus injuries are complex in nature caused in large by high impact traffic accidents which can lead to additional complications such as Complex Regional Pain Syndrome and even lead to amputation or the need for further surgical intervention. Treatment options to help repair the brachial plexus initially involve surgical intervention and post-surgery rehabilitation with medication to help with ongoing pain. Pain treatments used for these types of injuries are limited and differ in effectiveness. Paradigms utilising multimodal systems such as the one described in this paper based on virtual reality and robotics could yield results that are non-invasive and provide better rehabilitation outcomes for the sufferers. In this paper we present a single case study exploring whether Virtual Reality plus Haptic feedback have any practical potential for reducing upper limb pain and improving function in patients with brachial plexus injuries. The case study is presented with long standing complex combination of phantom limb and neuropathic pain. A decrease in perceived levels of pain was reported which amounts to a 50% reduction in pain from baseline and an improved range of motion. An examination of the sensory phantom map on the stump seems to indicate an early establishment of the thumb representation on the stump close to the area being stimulated with potential implications for prosthesis use.

Reducing the Risk and Impact of Brachial Plexus Injury Sustained From Prone Positioning-A Clinical Commentary.

INTRODUCTION: Prone positioning is deployed as a critical treatment for improving oxygenation in patients with Acute Respiratory Distress Syndrome. This regimen is currently highly prevalent in the COVID-19 pandemic. The pandemic has brought about increased concern about how best to safely avoid brachial plexus injuries when caring for unconscious proned patients. METHODS: A review of the published literature on brachial plexus injuries secondary to proning ventilated patients was performed. This was combined with a review of available international critical care guidelines in order to produce a succinct set of guidelines to aid critical care departments in reducing brachial plexus injuries during these challenging times. DISCUSSION: There is no one manner in which prone positioning an unconscious patient can be made universally safe. This paper provides 6 key steps to reducing the incidence of brachial plexus injuries while proning and suggests a safe and sensible management and referral pathway for the conscious patient in which a brachial plexus injury is identified. CONCLUSION: There is in truth no completely safe position for every patient and certainly there will be anomalies in anatomy that will predispose certain individuals to nerve injury. Thus the injury rate cannot be reduced to zero but an understanding of the principles of protection will inform those undertaking positioning.

Ulnar Nerve Entrapment at Elbow in an Adult Patient with Macrodactyly.

We describe a case of an adult patient presenting with cubital tunnel syndrome in the setting of previously undiagnosed macrodactyly. Early diagnosis and management of macrodactyly is important to help prevent symptoms associated with compromised peripheral nerves and reduce the likelihood of the permanent motor and sensory sequelae of prolonged nerve compression.

Granulocyte-macrophage colony-stimulating factor receptor expression in clinical pain disorder tissues and role in neuronal sensitization.

INTRODUCTION: Granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) is highly expressed in peripheral macrophages and microglia, and is involved in arthritis and cancer pain in animal models. However, there is limited information on GM-CSFR expression in human central nervous system (CNS), peripheral nerves, or dorsal root ganglia (DRG), particularly in chronic pain conditions. OBJECTIVES: Immunohistochemistry was used to quantify GM-CSFR expression levels in human tissues, and functional sensory effects of GM-CSF were studied in cultured DRG neurons. RESULTS: Granulocyte-macrophage colony-stimulating factor receptor was markedly increased in microglia at lesional sites of multiple sclerosis spinal cords (P = 0.01), which co-localised with macrophage marker CD68 (P = 0.009). In human DRG, GM-CSFR was expressed in a subset of small/medium diameter cells (30%) and few large cells (10%), with no significant change in avulsion-injured DRG. In peripheral nerves, there was a marked decrease in axonal GM-CSFR after chronic painful nerve injury (P = 0.004) and in painful neuromas (P = 0.0043); CD-68-positive macrophages were increased (P = 0.017) but did not appear to express GM-CSFR. Although control synovium showed absent GM-CSFR immunostaining, this was markedly increased in macrophages of painful osteoarthritis knee synovium. Granulocyte-macrophage colony-stimulating factor receptor was expressed in 17 ± 1.7% of small-/medium-sized cultured adult rat DRG neurons, and in 27 ± 3.3% of TRPV1-positive neurons. Granulocyte-macrophage colony-stimulating factor treatment sensitized capsaicin responses in vitro, which were diminished by p38 MAPK or TrkA inhibitors. CONCLUSION: Our findings support GM-CSFR as a therapeutic target for pain and hypersensitivity in clinical CNS and peripheral inflammatory conditions. Although GM-CSFR was decreased in chronic painful injured peripheral nerves, it could mediate CNS neuroinflammatory effects, which deserves study.

Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons.

INTRODUCTION: Glucagon like-peptide 1 receptor (GLP-1R) agonists diminish appetite and may contribute to the weight loss in inflammatory bowel disease (IBD). OBJECTIVES: The aim of this study was to determine, for the first time, the expression of GLP-1R by colon nerve fibres in patients with IBD, and functional effects of its agonists in cultured rat and human sensory neurons. METHODS: GLP-1R and other nerve markers were studied by immunohistochemistry in colon biopsies from patients with IBD (n = 16) and controls (n = 8), human dorsal root ganglia (DRG) tissue, and in GLP-1R transfected HEK293 cells. The morphological effects of incretin hormones oxyntomodulin, exendin-4 and glucagon were studied on neurite extension in cultured DRG neurons, and their functional effects on capsaicin and ATP signalling, using calcium imaging. RESULTS: Significantly increased numbers of colonic mucosal nerve fibres were observed in IBD biopsies expressing GLP-1R (p = 0.0013), the pan-neuronal marker PGP9.5 (p = 0.0008), and sensory neuropeptide CGRP (p = 0.0014). An increase of GLP-1R positive nerve fibres in IBD colon was confirmed with a different antibody to GLP-1R (p = 0.016). GLP-1R immunostaining was intensely positive in small and medium-sized neurons in human DRG, and in human and rat DRG cultured neurons. Co-localization of GLP-1R expression with neuronal markers in colon and DRG confirmed the neural expression of GLP-1R, and antibody specificity was confirmed in HEK293 cells transfected with the GLP-1R. Treatment with oxyntomodulin, exendin-4 and GLP-1 increased neurite length in cultured neurons compared with controls, but did not stimulate calcium influx directly, or affect capsaicin responses. However, exendin-4 significantly enhanced ATP responses in human DRG neurons. CONCLUSION: Our results show that increased GLP-1R innervation in IBD bowel could mediate enhanced visceral afferent signalling, and provide a peripheral target for therapeutic intervention. The differential effect of GLP-1R agonists on capsaicin and ATP responses in neurons suggest they may not affect pain mechanisms mediated by the capsaicin receptor TRPV1, but may enhance the effects of purinergic agonists.

Robotic therapy for phantom limb pain in upper limb amputees.

The system described in this paper combines virtual reality with haptic feedback to increase the level of immersion and invoke the sense of agency in patients with phantom limb pain with the aim of reducing perceived pain. This paper presents three case studies of an on-going clinical study. The initial results suggest an increased sense of embodiment of the virtual limb promotes a decrease in perceived levels of pain. The results strengthen the view that the cortical map does not fully "disappear" yet lays dormant.

Capsaicin 8% patch treatment for amputation stump and phantom limb pain: a clinical and functional MRI study.

PURPOSE: The aim of this study was to measure the efficacy of a single 60 min application of capsaicin 8% patch in reducing chronic amputation stump and phantom limb pain, associated hypersensitivity with quantitative sensory testing, and changes in brain cortical maps using functional MRI (fMRI) scans. METHODS: A capsaicin 8% patch (Qutenza) treatment study was conducted on 14 patients with single limb amputation, who reported pain intensity on the Numerical Pain Rating Scale ≥4/10 for chronic stump or phantom limb pain. Pain assessments, quantitative sensory testing, and fMRI (for the lip pursing task) were performed at baseline and 4 weeks after application of capsaicin 8% patch to the amputation stump. The shift into the hand representation area of the cerebral cortex with the lip pursing task has been correlated with phantom limb pain intensity in previous studies, and was the fMRI clinical model for cortical plasticity used in this study. RESULTS: The mean reduction in spontaneous amputation stump pain, phantom limb pain, and evoked stump pain were -1.007 (p=0.028), -1.414 (p=0.018), and -2.029 (p=0.007), respectively. The areas of brush allodynia and pinprick hypersensitivity in the amputation stump showed marked decreases: -165 cm2, -80% (p=0.001) and -132 cm2, -72% (p=0.001), respectively. fMRI analyses provided objective evidence of the restoration of the brain map, that is, reversal of the shift into the hand representation of the cerebral cortex with the lip pursing task (p<0.05). CONCLUSION: The results show that capsaicin 8% patch treatment leads to significant reduction in chronic pain and, particularly, in the area of stump hypersensitivity, which may enable patients to wear prostheses, thereby improving mobility and rehabilitation. Phantom limb pain ("central" pain) and associated brain plasticity may be modulated by peripheral inputs, as they can be ameliorated by the peripherally restricted effect of the capsaicin 8% patch.

Nociceptin/orphanin FQ receptor expression in clinical pain disorders and functional effects in cultured neurons.

The nociceptin/orphanin FQ peptide receptor (NOP), activated by its endogenous peptide ligand nociceptin/orphanin FQ (N/OFQ), exerts several effects including modulation of pain signalling. We have examined, for the first time, the tissue distribution of the NOP receptor in clinical visceral and somatic pain disorders by immunohistochemistry and assessed functional effects of NOP and µ-opioid receptor activation in cultured human and rat dorsal root ganglion (DRG) neurons. Quantification of NOP-positive nerve fibres within the bladder suburothelium revealed a remarkable several-fold increase in detrusor overactivity (P < 0.0001) and painful bladder syndrome patient specimens (P = 0.0014) compared with controls. In postmortem control human DRG, 75% to 80% of small/medium neurons (≤50 µm diameter) in the lumbar (somatic) and sacral (visceral) DRG were positive for NOP, and fewer large neurons; avulsion-injured cervical human DRG neurons showed similar numbers. NOP immunoreactivity was significantly decreased in injured peripheral nerves (P = 0.0004), and also in painful neuromas (P = 0.025). Calcium-imaging studies in cultured rat DRG neurons demonstrated dose-dependent inhibition of capsaicin responses in the presence of N/OFQ, with an IC50 of 8.6 pM. In cultured human DRG neurons, 32% inhibition of capsaicin responses was observed in the presence of 1 pM N/OFQ (P < 0.001). The maximum inhibition of capsaicin responses was greater with N/OFQ than µ-opioid receptor agonist DAMGO. Our findings highlight the potential of NOP agonists, particularly in urinary bladder overactivity and pain syndromes. The regulation of NOP expression in visceral and somatic sensory neurons by target-derived neurotrophic factors deserves further study, and the efficacy of NOP selective agonists in clinical trials.

Mechanisms underlying clinical efficacy of Angiotensin II type 2 receptor (AT2R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies.

BACKGROUND: The clinical efficacy of the Angiotensin II (AngII) receptor AT2R antagonist EMA401, a novel peripherally-restricted analgesic, was reported recently in post-herpetic neuralgia. While previous studies have shown that AT2R is expressed by nociceptors in human DRG (hDRG), and that EMA401 inhibits capsaicin responses in cultured hDRG neurons, the expression and levels of its endogenous ligands AngII and AngIII in clinical neuropathic pain tissues, and their signalling pathways, require investigation. We have immunostained AngII, AT2R and the capsaicin receptor TRPV1 in control post-mortem and avulsion injured hDRG, control and injured human nerves, and in cultured hDRG neurons. AngII, AngIII, and Ang-(1-7) levels were quantified by ELISA. The in vitro effects of AngII, AT2R agonist C21, and Nerve growth factor (NGF) were measured on neurite lengths; AngII, NGF and EMA401 effects on expression of p38 and p42/44 MAPK were measured using quantitative immunofluorescence, and on capsaicin responses using calcium imaging. RESULTS: AngII immunostaining was observed in approximately 75% of small/medium diameter neurons in control (n = 5) and avulsion injured (n = 8) hDRG, but not large neurons i.e. similar to TRPV1. AngII was co-localised with AT2R and TRPV1 in hDRG and in vitro. AngII staining by image analysis showed no significant difference between control (n = 12) and injured (n = 13) human nerves. AngII levels by ELISA were also similar in control human nerves (4.09 ± 0.36 pmol/g, n = 31), injured nerves (3.99 ± 0.79 pmol/g, n = 7), and painful neuromas (3.43 ± 0.73 pmol/g, n = 12); AngIII and Ang-(1-7) levels were undetectable (<0.03 and 0.05 pmol/g respectively). Neurite lengths were significantly increased in the presence of NGF, AngII and C21 in cultured DRG neurons. AngII and, as expected, NGF significantly increased signal intensity of p38 and p42/44 MAPK, which was reversed by EMA401. AngII mediated sensitization of capsaicin responses was not observed in the presence of MAP kinase inhibitor PD98059, and the kinase inhibitor staurosporine. CONCLUSION: The major AT2R ligand in human peripheral nerves is AngII, and its levels are maintained in injured nerves. EMA401 may act on paracrine/autocrine mechanisms at peripheral nerve terminals, or intracrine mechanisms, to reduce neuropathic pain signalling in AngII/NGF/TRPV1-convergent pathways.

Diagnostic value of magnetic resonance imaging in thoracic outlet syndrome.

PURPOSE. To evaluate the diagnostic value of magnetic resonance imaging (MRI) in thoracic outlet syndrome (TOS). METHODS. Medical records of 30 women and 10 men aged 18 to 68 (mean, 38) years who presented with unilateral (n=35) and bilateral (n=5) TOS and underwent 42 surgical decompressions of the right (n=23) and left (n=19) sides were reviewed. MRI findings were compared with intra-operative findings to evaluate the diagnostic value of MRI. RESULTS. MRI findings correlated poorly with intra-operative findings. Of the 42 cases, MRI and intra-operative findings were matched in 17 and not matched in 25. MRI appeared normal but intra-operative findings were in fact positive for TOS in 23 of 24 cases. The sensitivity and specificity of MRI in diagnosing TOS were 41% and 33%, respectively, whereas its positive and negative predictive values were 89% and 4%, respectively. CONCLUSION. Sensitivity and specificity of MRI in diagnosing TOS are low. Diagnosis should be based on a holistic approach including history, clinical examination, and radiological findings.

Late presentation of a partial median nerve palsy following a Gartland III supracondylar humeral fracture.

A 28-year-old male patient was referred to the Peripheral Nerve Injury Unit at the Royal National Orthopaedic Hospital for evaluation and treatment of a neuropathic type pain he had developed in his right arm. Some twenty years previously, he had sustained a Gartland type III supracondylar humeral fracture with what was thought clinically to be an anterior interosseous nerve palsy. The fracture was reduced and the nerve palsy subsequently recovered with non operative measures. At his subsequent delayed presentation, surgical exploration revealed that the median nerve epineurium was embedded within the bone at the level of the previous fracture. A good clinical result was obtained following neurolysis. The case report highlights a late presentation of median nerve palsy following interposition of the neural structure within the reduced distal humeral fracture site; it shows that delayed surgery can be effective.

Increased levels of SV2A botulinum neurotoxin receptor in clinical sensory disorders and functional effects of botulinum toxins A and E in cultured human sensory neurons.

BACKGROUND: There is increasing evidence that botulinum neurotoxin A may affect sensory nociceptor fibers, but the expression of its receptors in clinical pain states, and its effects in human sensory neurons, are largely unknown. METHODS: We studied synaptic vesicle protein subtype SV2A, a receptor for botulinum neurotoxin A, by immunostaining in a range of clinical tissues, including human dorsal root ganglion sensory neurons, peripheral nerves, the urinary bladder, and the colon. We also determined the effects of botulinum neurotoxins A and E on localization of the capsaicin receptor, TRPV1, and functional sensitivity to capsaicin stimuli in cultured human dorsal root ganglion neurons. RESULTS: Image analysis showed that SV2A immunoreactive nerve fibers were increased in injured nerves proximal to the injury (P = 0.002), and in painful neuromas (P = 0.0027); the ratio of percentage area SV2A to neurofilaments (a structural marker) was increased proximal to injury (P = 0.0022) and in neuromas (P = 0.0001), indicating increased SV2A levels in injured nerve fibers. In the urinary bladder, SV2A nerve fibers were found in detrusor muscle and associated with blood vessels, with a significant increase in idiopathic detrusor over-activity (P = 0.002) and painful bladder syndrome (P = 0.0087). Colon biopsies showed numerous SV2A-positive nerve fibers, which were increased in quiescent inflammatory bowel disease with abdominal pain (P = 0.023), but not in inflammatory bowel disease without abdominal pain (P = 0.77) or in irritable bowel syndrome (P = 0.13). In vitro studies of botulinum neurotoxin A-treated and botulinum neurotoxin E-treated cultured human sensory neurons showed accumulation of cytoplasmic vesicles, neurite loss, and reduced immunofluorescence for the heat and capsaicin receptor, TRPV1. Functional effects included dose-related inhibition of capsaicin responses on calcium imaging after acute treatment with botulinum neurotoxins A and E. CONCLUSION: Differential levels of SV2A protein expression in clinical disorders may identify potential new targets for botulinum neurotoxin therapy. In vitro studies indicate that treatment with botulinum neurotoxins A and E may affect receptor expression and nociceptor function in sensory neurons.

Spinal cord stimulation for recurrent painful neuromas of the foot.

The authors report the case of a patient affected by recurrent neuromas of the interdigital nerves of the left foot that appeared after surgery for Morton's disease. Implantation of spinal cord stimulation (SCS) system was performed after three unsuccessful surgical revisions, which demonstrated the presence of multiple neuromas growing at endings of the stumps of the nerves and fasciculi. The patient developed chronic neuropathic pain localized within the third metatarsal region of the left foot. Conservative treatments failed and autonomous gait became impossible. SCS immediately abolished pain and the patient was able to perform her normal daily activities within 1 month. At our knowledge, this is the first report in literature of SCS successfully employed for recurrent and refractory pain due to Morton's neuroma.

Congenital lower brachial plexus palsy due to cervical ribs.

Congenital brachial plexus palsy (CBPP) usually occurs secondarily to intrapartum trauma, but this is not always the case. Cervical ribs have previously been reported to increase the risk of CBPP in association with birth trauma. We report the cases of two children (one female, one male) with congenital lower brachial plexus palsy in whom the presence of non-ossified cervical ribs was the only identified risk factor. In the female child magnetic resonance imaging (MRI) of the brain, spinal cord, and brachial plexus revealed no abnormality except for the presence of bilateral cervical ribs at the level of the seventh cervical (C7) vertebra. Chest radiography was normal, which suggested that the cervical ribs identified on the MRI were fibrous bands or cartilaginous ribs rather than ossified ribs. In the male child, MRI of the spine and brachial plexus was normal but he was noted to have bilateral cervical ribs at C7. These were not identifiable on chest radiography and, therefore, are likely to reflect fibrous bands or cartilaginous ribs.

The value of preoperative and intraoperative electromyography in the management of obstetric brachial plexus injury.

The treatment of obstetric brachial plexus palsy (OBPP) with neuroma-in-continuity is controversial. The recent literature advocates excision of neuroma-in-continuity in OBPP and repair with nerve graft irrespective of its neurophysiological conductivity. This approach risks sacrificing the regenerating axons, and the result has not yet been proven to be superior to neurolysis alone. In this case report, the authors aim to outline their strategy of using the combination of preoperative and intraoperative clinical and neurophysiological findings to aid their decision making. The lack of upper trunk recovery and the unfavorable preoperative neurophysiological findings in a child with Narakas Group 4 OBPP at 5 months of age prompted an urgent exploration with the intention of performing neurotization. This procedure was abandoned and neurolysis was performed due to the favorable intraoperative neurophysiological findings. At 4 years of age, the child scored 12 of 15 on Mallet classification and has an excellent range of movement. No secondary operation was needed. The authors hope to highlight the idea that the surgical option for neurolysis alone should be kept open and that intraoperative electromyography can be a valuable tool to add to the surgeon's armamentarium.

Cytosine arabinoside affects the heat and capsaicin receptor TRPV1 localisation and sensitivity in human sensory neurons.

BACKGROUND: Cytosine arabinoside (Ara C) is a useful chemotherapy agent, used for treating acute myeloid leukaemia, although it may be associated with side effects including painful neuropathy. It is also used for in vitro neuronal studies to limit the proliferation of non-neuronal cells and thereby select nondividing neuronal cells. We studied the effects of Ara C on human dorsal root ganglion (DRG) neurons, especially the expression and sensitivity of the ion channel TRPV1, which responds to noxious heat and capsaicin and is a key mediator of neuropathic pain. METHODS: Human DRG neurons were cultured with or without Ara C for 2 weeks, after which Ara C was discontinued. Double immunostaining for the regenerative neuronal marker Gap43 and the capsaicin receptor TRPV1 showed that the normal membrane-bound localisation of TRPV1 was absent in neurons with Ara C treatment, and as expected there was massive diminution of dividing non-neuronal cells. Calcium imaging studies showed that during exposure to Ara C the neurons lost responsiveness to capsaicin, although ionomycin responses were intact, indicating general cell viability and responsiveness. Between 2 days and up to 3 weeks after removal of Ara C, the neuronal responses to capsaicin were regained and were observed to be four times (P = 0.0008, Student's t-test) that of controls, but there was only a gradual recovery of non-neuronal cells. Three to six weeks after Ara C removal, capsaicin responses were comparable to controls. CONCLUSIONS: It is postulated that Ara C treatment blocked insertion of TRPV1 in the cell membrane, resulting in accumulation of the receptors in the cytoplasm, loss of capsaicin sensitivity, and membrane-bound immunostaining, which was restored with a rebound on withdrawal of Ara C. The observed pattern of loss of capsaicin sensitivity, followed by hypersensitivity and recovery, appears to reflect some of the features observed in chemotherapy-induced neuropathy, and may provide a model for developing new treatments and prophylaxis.

Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy.

BACKGROUND: Transient receptor potential (TRP) receptors expressed by primary sensory neurons mediate thermosensitivity, and may play a role in sensory pathophysiology. We previously reported that human dorsal root ganglion (DRG) sensory neurons co-expressed TRPV1 and TRPV3, and that these were increased in injured human DRG. Related receptors TRPV4, activated by warmth and eicosanoids, and TRPM8, activated by cool and menthol, have been characterised in pre-clinical models. However, the role of TRPs in common clinical sensory neuropathies needs to be established. METHODS: We have studied TRPV1, TRPV3, TRPV4, and TRPM8 in nerves (n = 14) and skin from patients with nerve injury, avulsed dorsal root ganglia (DRG) (n = 11), injured spinal nerve roots (n = 9), diabetic neuropathy skin (n = 8), non-diabetic neuropathic nerve biopsies (n = 6), their respective control tissues, and human post mortem spinal cord, using immunohistological methods. RESULTS: TRPV1 and TRPV3 were significantly increased in injured brachial plexus nerves, and TRPV1 in hypersensitive skin after nerve repair, whilst TRPV4 was unchanged. TRPM8 was detected in a few medium diameter DRG neurons, and was unchanged in DRG after avulsion injury, but was reduced in axons and myelin in injured nerves. In diabetic neuropathy skin, TRPV1 expressing sub- and intra-epidermal fibres were decreased, as was expression in surviving fibres. TRPV1 was also decreased in non-diabetic neuropathic nerves. Immunoreactivity for TRPV3 was detected in basal keratinocytes, with a significant decrease of TRPV3 in diabetic skin. TRPV1-immunoreactive nerves were present in injured dorsal spinal roots and dorsal horn of control spinal cord, but not in ventral roots, while TRPV3 and TRPV4 were detected in spinal cord motor neurons. CONCLUSION: The accumulation of TRPV1 and TRPV3 in peripheral nerves after injury, in spared axons, matches our previously reported changes in avulsed DRG. Reduction of TRPV1 levels in nerve fibres in diabetic neuropathy skin may result from the known decrease of nerve growth factor (NGF) levels. The role of TRPs in keratinocytes is unknown, but a relationship to changes in NGF levels, which is produced by keratinocytes, deserves investigation. TRPV1 represents a more selective therapeutic target than other TRPs for pain and hypersensitivity, particularly in post-traumatic neuropathy.