Penile erectile dysfunction after brachial plexus root avulsion injury in rats

Our previous studies have demonstrated that some male patients suffering from brachial plexus injury, particularly brachial plexus root avulsion, show erectile dysfunction to varying degrees. However, the underlying mechanism remains poorly understood. In this study, we evaluated the erectile function after establishing brachial plexus root avulsion models with or without spinal cord injury in rats. After these models were established, we administered apomorphine （via a sub- cutaneous injection in the neck） to observe changes in erectile function. Rats subjected to simple brachial plexus root avulsion or those subjected to brachial plexus root avulsion combined with spinal cord injury had significantly fewer erections than those subjected to the sham operation. Expression of neuronal nitric oxide synthase did not change in brachial plexus root avulsion rats. However, neuronal nitric oxide synthase expression was significantly decreased in brachial plexus root avulsion ＋ spinal cord injury rats. These findings suggest that a decrease in neuronal nitric oxide synthase expression in the penis may play a role in erectile dysfunction caused by the combi- nation of brachial plexus root avulsion and spinal cord injury.     

Effect of Co-Morbid Conditions on Persistent Neuropathic Pain after Brachial Plexus Injury in Adult Patients

MethodsThe medical records of patients diagnosed with BPI referred to a pain center between 2006 and 2010 were reviewed for 2 years retrospectively. Data regarding patient demographics, injury and surgical profiles, characteristics of NeuP and its severity, and treatment received were compared between patients with and without manifesting co-morbid conditions. The NeuP and pain intensity assessments were based on the DN4 questionnaire and a numerical rating scale, respectively.ResultsOf the 45 patients studied, 24 patients presented with one of the following co-morbid conditions: myofascial pain (21%), psychiatric disorder (17%), phantom limb pain (4%), complex regional pain syndrome (21%), and insomnia (37%). Tramadol was required by 20 patients with co-morbidity and, 9 patients without co-morbidity (p<0.001). The mean pain score after 2 years was higher in patients with co-morbidity than in those without co-morbidity (p<0.05).ConclusionsPersistent pain following BPI was more common in patients manifesting other painful conditions or psychiatric co-morbidity. A higher proportion of the patients in the co-morbid group required tramadol as a second-line of agent for pain relief.     

Molecular mechanisms underlying the effects of acupuncture on neuropathic pain

Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity following chronic constriction injury, es-pecially electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function.     

Resolving the contributions of anaesthesia,surgery, and nerve injury on brain derived neurotrophic factor expression in the medial prefrontal cortex of male rats in the CCI model of neuropathic pain

The medial prefrontal cortex (mPFC) is critical for selecting and shaping complex behavioral responses. In rodent models of neuropathic pain there is evidence for both structural and functional changes in the mPFC. Brain derived neurotrophic factor (BDNF) plays a critical role in the normal functioning of the mPFC. It has been suggested that the disruption of complex behaviors and mood seen in some neuropathic pain patients is mediated in part by alterations of BDNF in this cortical region. In Sprague‐Dawley rats, mPFC levels of BDNF and TrkB mRNA and protein, were quantified and compared to controls (n = 24) 6 days after either: (a) halothane (1.5%) anaesthesia (n = 12), (b) sham surgery under halothane (n = 12), (c) sciatic nerve chronic constriction injury under halothane (n = 48). The social behaviors of the rats were quantified daily during the experimental period. Halothane anaesthesia increased BDNF and TrkB mRNA bilaterally. These increases were reversed in rats that underwent sham surgical and nerve injury procedures. Further, halothane anaesthesia, surgical procedures, and nerve injury each decreased BDNF protein levels. These results reveal a marked and distinct BDNF expression profile in the mPFC of rats that have undergone each stage of the procedure to produce neuropathic pain by chronic constriction injury of the sciatic nerve. The highly sensitive nature of neurotrophic signalling to general anaesthesia in the mature neuronal circuit of the adult rat brain highlights the importance of careful evaluation and interpretation of data evaluating the effects of experimental procedures on neural substrates.     

Assessment of obstetric brachial plexus injury with preoperative ultrasound

Introduction: Tools used in the assessment of obstetric brachial plexus injuries (OBPIs) have traditionally included electrodiagnostic studies, computerized tomography with myelography, and MRI. However, the utility of ultrasound (US) in infants for such assessment has not been extensively examined. Methods: This retrospective case series reports the preoperative brachial plexus US findings in 8 patients with OBPI and compares US with intraoperative findings. When available, the preoperative US was compared with the preoperative MRI. Results: US revealed abnormalities in all 8 patients. Although MRI detected abnormalities in the majority of patients, US provided accurate information regarding severity and anatomic location of injury in some patients. Conclusions: US is a relatively inexpensive, noninvasive, painless diagnostic modality that can be used to assess OBPI. This case series suggests that US is a valuable adjunct to current diagnostic modalities. Muscle Nerve 53 : 946–950, 2016     

Full-length phrenic nerve transfer as the treatment for brachial plexus avulsion injury to restore wrist and finger extension

Introduction: The functional restoration of wrist and finger extension after complete brachial plexus avulsion injury remains an unsolved problem. We conducted a prospective study to elucidate a new method for resolving this injury. Methods: Six patients with complete brachial plexus avulsion injury underwent a new surgical procedure in which the full‐length phrenic nerve was transferred to the medial portion of the radial nerve at the level of the latissimus dorsi insertion via endoscopic thoracic surgery. Results: In 5 patients, extensor carpi ulnaris and extensor carpi radialis strength recovered to Medical Research Council grade ≥M3, and in 4 patients extensor digitorum strength recovered to ≥M3. Conclusions: Neurotization of phrenic nerve to the medial portion of the radial nerve at the level of latissimus dorsi insertion is a feasible means of restoring wrist and finger extension in cases of complete brachial plexus avulsion injury. Muscle Nerve 45: 39–42, 2012     

ISP and PAP4 peptides promote motor functional recovery after peripheral nerve injury

Both intracellular sigma peptide(ISP) and phosphatase and tensin homolog agonist protein(PAP4) promote nerve regeneration and motor functional recovery after spinal cord injury. However, the role of these two small peptides in peripheral nerve injury remains unclear. A rat model of brachial plexus injury was established by crush of the C6 ventral root. The rats were then treated with subcutaneous injection of PAP4(497 μg/d, twice per day) or ISP(11 μg/d, once per day) near the injury site for 21 successive days. After ISP and PAP treatment, the survival of motoneurons was increased, the number of regenerated axons and neuromuscular junctions was increased, muscle atrophy was reduced, the electrical response of the motor units was enhanced and the motor function of the injured upper limbs was greatly improved in rats with brachial plexus injury. These findings suggest that ISP and PAP4 promote the recovery of motor function after peripheral nerve injury in rats. The animal care and experimental procedures were approved by the Laboratory Animal Ethics Committee of Jinan University of China(approval No. 20111008001) in 2011.     

Correlation between the cumulative analgesic effect of electroacupuncture intervention and synaptic plasticity of hypothalamic paraventricular nucleus neurons in rats with sciatica

In the present study, a rat model of chronic neuropathic pain was established by ligation of the sciatic nerve and a model of learning and memory impairment was established by ovariectomy to investigate the analgesic effect of repeated electroacupuncture stimulation at bilateral Zusanli (ST36) and Yanglingquan (GB34). In addition, associated synaptic changes in neurons in the paraventricular nucleus of the hypothalamus were examined. Results indicate that the thermal pain threshold (paw withdrawal latency) was significantly increased in rats subjected to 2-week electroacupuncture intervention compared with 2-day electroacupuncture, but the analgesic effect was weakened remarkably in ovariectomized rats with chronic constrictive injury. 2-week electroacupuncture intervention substantially reversed the chronic constrictive injury-induced increase in the synaptic cleft width and thinning of the postsynaptic density. These findings indicate that repeated electroacupuncture at bilateral Zusanli and Yanglingquan has a cumulative analgesic effect and can effectively relieve chronic neuropathic pain by remodeling the synaptic structure of the hypothalamic paraventricular nucleus.     

Avulsion injury of the rat brachial plexus triggers hyperalgesia and allodynia in the hindpaws: a new model for the study of neuropathic pain

In the present study, we sought to characterise a behavioural model of persistent peripheral neuropathic pain produced by avulsion of the right brachial plexus in rats. In addition, we compared the effects of avulsion with those of ligation or crush injury of the brachial plexus. Avulsion and, to a lesser extent, ligation and crushing of brachial plexus caused a long-lasting (up to 90 days) and highly reproducible mechanical hyperalgesia, in both ipsilateral and contralateral hindpaws. However, the same injury did not produce thermal hyperalgesia. The avulsion and, to a lesser extent, ligation and crushing of the brachial plexus elicited a significant and long-lasting (up to 90 days) ipsilateral and contralateral cold and mechanical allodynia. Furthermore, the brachial plexus injury caused a significant decrease in functional activity of the forepaws as assessed in the grasping strength test, but did not alter the locomotor activity of the rats in the open field test in comparison with control or sham groups. Taken together these results show that avulsion of the brachial plexus in rat produces persistent mechanical and cold allodynia and mechanical hyperalgesia, and might represent a valuable method for understanding the mechanisms underlying the aetiology of neuropathic pain.     

Pharmacological characterisation of the rat brachial plexus avulsion model of neuropathic pain

Recently, our laboratory has proposed the avulsion of rat brachial plexus as a new and reliable model for the study of neuropathic pain. In this model, the neuropathy can be detected even at distant sites from the injury, both in ipsilateral and contralateral hindpaws. The purpose of this study was to pharmacologically characterise this behavioural model of persistent peripheral neuropathic pain by assessing the effects of several analgesic drugs currently used in clinical practice. For this purpose, the effects of these drugs on the mechanical and cold allodynia were analysed 20-40 days after rat brachial plexus avulsion. Injection of saline, administered by the same route as the other drugs, did not significantly affect the nociceptive threshold either in sham-operated or in neuropathic rats. However, administration of the opioid analgesic morphine (5 mg/kg, s.c.), the alpha2 adrenoceptor agonist clonidine (300 microg/kg, i.p.), the NMDA receptor antagonist ketamine (25 mg/kg, i.p.) or the anticonvulsant drug gabapentin (70 mg/kg, p.o.) consistently reduced both mechanical and cold allodynia following avulsion of rat brachial plexus. The administration of the selective COX-2 inhibitor celecoxib (10 mg/kg, p.o.) blocked mechanical allodynia, but not cold allodynia, whereas the sodium channel blocker lidocaine (40 mg/kg, i.p.) attenuated only cold allodynia. The non-steroidal anti-inflammatory drug diclofenac (100 mg/kg, i.p.), the steroidal anti-inflammatory dexamethasone (1.5 mg/kg, i.p.) and the antidepressant imipramine (10 mg/kg, i.p.) all failed to significantly attenuate both mechanical and cold allodynia in the rats following avulsion of brachial plexus. These findings suggest that avulsion-associated mechanical and cold allodynia, two classic signs of persistent neuropathic pain, were consistently prevented by several analgesics currently available in clinical practice, namely morphine, clonidine, ketamine and gabapentin, and to a lesser extent by celecoxib and lidocaine. Therefore, this new proposed model of persistent nociception seems to be suitable for the study of the underlying mechanisms involved in neuropathic pain and for the identification of potential clinically relevant drugs to treat this aspect of peripheral neuropathy.     

Restoration and protection of brachial plexus injury： hot topics in the last decade

Brachial plexus injury is frequently induced by injuries, accidents or birth trauma. Upper limb function may be partially or totally lost after injury, or left permanently disabled. With the de- velopment of various medical technologies, different types of interventions are used, but their effectiveness is wide ranging. Many repair methods have phasic characteristics, i.e., repairs are done in different phases. This study explored research progress and hot topic methods for pro- tection after brachial plexus injury, by analyzing 1,797 articles concerning the repair of brachial plexus injuries, published between 2004 and 2013 and indexed by the Science Citation Index database. Results revealed that there are many methods used to repair brachial plexus injury, and their effects are varied. Intervention methods include nerve transfer surgery, electrical stimula- tion, cell transplantation, neurotrophic factor therapy and drug treatment. Therapeutic methods in this field change according to the hot topic of research.     

TRPM2 participates the transformation of acute pain to chronic pain during injury‐induced neuropathic pain

Transient receptor melastatin 2 (TRPM2) is a nonselective Ca²⁺‐permeable cation channel highly expressed in brain and other tissues. Studies showed that TRPM2 contributed to the induction of inflammatory cytokine and chemokine of immune cells, resulted in neuropathic pain. However, how TRPM2 regulates neuropathic pain is not clear. The sciatic nerve chronic constriction injury (CCI) rat model was used to induce chronic neuropathic pain. The RNA and protein level of TRPM2 was detected with real‐time PCR and western blot. SiRNA targeting TRPM2 was used to knockdown the expression of TRPM2. Reactive oxygen species (ROS) levels were determined using H2DCFDA assay and NO production was analyzed by measuring the accumulated level of its stable metabolite (nitrite). We found that CCI significantly increased TRPM2 expression in dorsal root ganglion and spinal cord. Knockdown TRPM2 in early phase after CCI alleviated injury‐induced neuropathic pain. Mechanistically, we demonstrated that TRPM2 knockdown drastically inhibited the iNOS expression and NO generation, with decreased ROS generation in CCI rat. TRPM2 participates in the transformation of acute pain to chronic pain during injury‐induced neuropathic pain, which might serve as a potential therapeutic target for neuropathic pain.     

Histone deacetylase inhibition inhibits brachial plexus avulsion‐induced neuropathic pain

Introduction: Neuropathic pain induced by brachial plexus avulsion (BPA) is a pathological condition. We hypothesized that inhibition of histone deacetylase (HDAC) could suppress BPA‐induced neuropathic pain through inhibition of transient reception potential (TRP) overexpression and protein kinase B (Akt)‐mediated mammalian target of rapamycin (mTOR) activation. Methods: We generated a rat BPA model; administered HDAC inhibitor tricostatin A (TSA) for 7 days postsurgery; and assessed the effects on HDAC expression, Akt phosphorylation, neuroinflammation, and mTOR activation. Results: TSA treatment alleviated BPA‐induced mechanical hyperalgesia, suppressed Akt phosphorylation, and increased HDAC. We found suppressed proinflammatory cytokine levels, TRPV1 and TRPM8 expression, and mTOR activity in TSA‐treated BPA rats. Discussion: Our results suggest that altered HDAC and Akt signaling are involved in BPA‐induced neuropathic pain and that inhibition of HDAC could be an effective therapeutic approach in reducing neuropathic pain. Muscle Nerve 58 : 434–440, 2018     

Electroacupuncture stimulation of the brachial plexus trunk on the healthy side promotes brain-derived neurotrophic factor mRNA expression in the ischemic cerebral cortex of a rat model of cerebral ischemia/reperfusion injury

A rat model of cerebral ischemia/reperfusion was established by suture occlusion of the left middle cerebral artery. In situ hybridization results showed that the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic rat cerebral cortex increased after cerebral ischemia/ reperfusion injury. Low frequency continuous wave electroacupuncture (frequency 2-6 Hz, current intensity 2 mA) stimulation of the brachial plexus trunk on the healthy (right) side increased the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic cerebral cortex 14 days after cerebral ischemia/reperfusion injury. At the same time, electroacupuncture stimulation of the healthy brachial plexus truck significantly decreased neurological function scores and alleviated neurological function deficits. These findings suggest that electroacupuncture stimulation of the brachial plexus trunk on the healthy (right) side can greatly increase brain-derived neurotrophic factor mRNA expression and improve neurological function.     

Pain,referred sensations,and involuntary muscle movements in brachial plexus injury

Finnerup NB, Norrbrink C, Fuglsang‐Frederiksen A, Terkelsen AJ, Hojlund AP, Jensen TS. Pain, referred sensations, and involuntary muscle movements in brachial plexus injury.
Acta Neurol Scand: 2010: 121: 320–327.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – Examination of the relationship between pain, sensory hypersensitivity, referred sensations and involuntary muscle jerks in patients with brachial plexus injury. Materials and methods – Fourteen patients with brachial plexus lesions were included. Spontaneous background and paroxysmal pain and mechanically and thermally evoked pain were recorded. Areas with sensory hypersensitivity and referred pain were mapped on a body chart. This was supplemented by electrophysiological analysis in three patients. Results – Sensory hypersensitivity and areas with pinprick‐induced referred phantom sensations were present in adjacent dermatomes. There was no clear relationship between chronic neuropathic pain and referred sensations, but there was a correlation between pain paroxysms and sensory hypersensitivity in dermatomes adjacent to deafferented areas. In three patients, simultaneous referred sensations and short latency motor action potentials ipsilateral to the denervated side suggested origin at subcortical sites. Conclusion – The study suggests a possible role of a spinal generator for sensory hypersensitivity and referred sensations following denervation.     

Transplantation of human amniotic epithelial cells repairs brachial plexus injury： pathological and biomechanical analyses

A brachial plexus injury model was established in rabbits by stretching the C6 nerve root. Imme- diately after the stretching, a suspension of human amniotic epithelial cells was injected into the injured brachial plexus. The results of tensile mechanical testing of the brachial plexus showed that the tensile elastic limit strain, elastic limit stress, maximum stress, and maximum strain of the injured brachial plexuses were significantly increased at 24 weeks after the injection. The treatment clearly improved the pathological morphology of the injured brachial plexus nerve, as seen by hematoxylin eosin staining, and the functions of the rabbit forepaw were restored. These data indicate that the injection of human amniotic epithelial cells contributed to the repair of brachial plexus injury, and that this technique may transform into current clinical treatment strategies.     

Increased miR‐195 aggravates neuropathic pain by inhibiting autophagy following peripheral nerve injury

Following peripheral nerve injury (PNI) microglia proliferates and adopts inflammation that contributes to development and maintenance of neuropathic pain. miRNAs and autophagy are two important factors in the regulation of inflammation. However, little is known about whether miRNAs regulate neuroinflammation and neuropathic pain by controlling autophagy. In the study, we demonstrated that miR‐195 levels were markedly increased in rats subjected to L5 spinal nerve ligation (SNL). Upregulated miR‐195 was also found in spinal microglia of rats with SNL. The overexpression of miR‐195 contributed to lipopolysaccharide‐induced expression of proinflammatory cytokines IL‐1β, TNF‐α, and iNOS in cultured microglia. Upregulated miR‐195 also resulted in increased mechanical and cold hypersensitivity after PNI, whereas miR‐195 inhibition reduced mechanical and cold sensitivity. We further demonstrated that PNI significantly inhibited microglial autophagy activation, whereas miR‐195 inhibitor treatment increased autophagy activation and suppressed neuroinflammation in vivo and in vitro. More important, autophagy inhibition impaired miR‐195 inhibitor‐induced downregulation of neuroinflammation and neuropathic pain. Additionally, ATG14 was identified as the functional target of miR‐195. Conclusions: These data demonstrated that miR‐195/autophagy signaling represents a novel pathway regulating neuroinflammation and neuropathic pain, thus offering a new target for therapy of neuropathic pain.     

Percutaneous Implantation of a Brachial Plexus Electrode for Management of Pain Syndrome Caused by a Traction Injury

Introduction. Intractable pain in the affected arm is a common sequel to severe traction lesions of the brachial plexus. Its management presents a challenge. Existing interventional therapies are not effective for the intractable pain from brachial plexus traction lesions, in the long term. Spinal cord stimulation is indicated for the relief of pain following peripheral nerve injury, but has its limitations and, in the UK, is restricted only to specialized centers. Peripheral neuromodulation is widely practiced noninvasively as transcutaneous electrical nerve stimulation and more recently, both as external neuromodulation and, invasively, using a surgical procedure with restricted indications. Methods. We report here a single case report of the successful management of intractable pain of uncertain pathology following traction injury of the shoulder and brachial plexus with the percutaneous implantation of a permanent stimulating electrode via a stimulating needle to the brachial plexus using the posterior route at the interscalene level. Results. Stimulation of the brachial plexus in this one patient has resulted in excellent pain control and unexpected beneficial sensory and motor changes in the arm of the patient. Conclusions. We cautiously conclude that percutaneous implantation of a stimulating electrode to the brachial plexus via a stimulating needle is a relatively simple procedure when compared to surgical implantation and, as shown in our case, very effective.     

Nerve transfer helps repair brachial plexus injury by increasing cerebral cortical plasticity

In the treatment of brachial plexus injury, nerves that are functionally less important are transferred onto the distal ends of damaged crucial nerves to help recover neuromuscular function in the target region. For example, intercostal nerves are transferred onto axillary nerves, and accessory nerves are transferred onto suprascapular nerves, the phrenic nerve is transferred onto the musculocutaneous nerves, and the contralateral C7 nerve is transferred onto the median or radial nerves. Nerve transfer has become a major method for reconstructing the brachial plexus after avulsion injury. Many experiments have shown that nerve transfers for treatment of brachial plexus injury can help reconstruct cerebral cortical function and increase cortical plasticity. In this review article, we summarize the recent progress in the use of diverse nerve transfer methods for the repair of brachial plexus injury, and we discuss the impact of nerve transfer on cerebral cortical plasticity after brachial plexus injury.