Pain affect disrupted in children with posterior cerebellar tumor resection.

Objectives: Damage to the posterior cerebellum can cause affective deficits in patients. In adults, cerebellar infarcts result in thermal hyperalgesia and affect descending modulation of pain. This study evaluated the effect of resection of low-grade cerebellar tumors on pain processing in human children. Methods: Twelve pediatric patients treated with surgery only for low-grade gliomas (8 females, 4 males; mean age = 13.8 ± 5.6) and twelve matched controls (8 females, 4 males; mean age = 13.8 ± 5.7) were evaluated using quantitative sensory testing and fMRI. Five patients had tumors localized to posterior cerebellar hemispheres, henceforth identified as Crus Patients. Results: Crus Patients had significantly lower pain tolerance to a cold pressor test than controls. No significant differences were detected between subject groups for heat and cold detection thresholds (HDT, CDT), and heat and cold pain thresholds (HPT, CPT). Crus Patients also showed significantly decreased fMRI responses to painful heat in anterior insula, which has been associated with pain affect. Interpretation: Damage to posterior cerebellar hemispheres disrupted affective pain processing and endogenous pain modulation, resulting in decreased pain tolerance to suprathreshold noxious stimuli. This suggests that surgical resection of this region in children may increase the risk of developing pain disorders.

Treatment of Hand Allodynia Resulting from Wrist Cutting with Radial and Ulnar Artery Perforator Adipofascial Flaps.

In this article, we report two cases in which recurrent adhesive hand neuropathy with allodynia were successfully treated with radial and ulnar artery adipofascial perforator flap coverage. Treatment of recurrent neuropathy, such as recurrent carpal tunnel syndrome and re-adhesion after neurolysis using free and pedicle flaps to cover the nerves, has been reported to show good results. However, for severe painful nerve disorders, such as complex regional pain syndrome, the efficacy of this treatment was unclear. We present two cases diagnosed with recurrent adhesive hand neuropathy with allodynia, resulting from wrist cutting; these cases were treated with neurolysis and flap coverage with good results and no recurrence. This suggests that neurolysis and flap coverage are effective methods for treating complex regional pain syndrome.

Eccrine spiradenoma mimicking a painful traumatic neuroma: case report.

Diagnosing and treating patients with persistent neuropathic pain associated with peripheral nerve lesions can be challenging. The authors report the rare case of a painful eccrine spiradenoma treated as a traumatic neuroma for many years because of a history of acute trauma, the presence of a tender palpable mass, and symptoms of allodynia. Surgical excision of the neoplasm completely relieved the pain and hypersensitivity that 2 prior surgeries and other nonsurgical treatments failed to resolve. The diagnosis of eccrine spiradenoma was not established until resection and histopathological analysis of the tissue. This case highlights the need to develop and consider an extensive list of differential diagnoses, including eccrine spiradenoma, for peripheral nerve lesions that fail to respond to treatment.

Role of CRF1 receptor in post-incisional plasma extravasation and nociceptive responses in mice.

The corticotropin-releasing factor (CRF) is involved in a number of physiological functions including pain perception. The purpose of this study was to evaluate the role of CRF1 receptor in the long-lasting post-surgical changes in somatic nociceptive thresholds and in local inflammatory responses, using genetically engineered mice lacking functional CRF1 receptor. Animals underwent a plantar incision under anaesthesia with remifentanil (80µg/kg s.c.) and sevoflurane. Mechanical thresholds (von Frey) and plasma extravasation (Evan's blue) were evaluated at different time points. On postoperative day 20, mechanical thresholds had returned to baseline in CD1 mice (3.07±6.21%), while B6,129CRHtklee mice presented significant hyperalgesia, which was similar in wild-type (WT) (-29.81±8.89%) and CRF1 receptor knockout (KO) (-37.10±10.75%) mice, showing strain differences. The administration of naloxone (1mg/kg, s.c.) on postoperative day 21 produced hyperalgesia revealing surgery-induced latent pain sensitization. The extent of hyperalgesia was greater in KO versus WT mice, suggesting a role of CRF1 receptors in the upward modulation of endogenous opioid release. Furthermore, two days after surgery, plasma extravasation returned to baseline in WT mice but remained elevated in KO mice. In non-manipulated B6,129CRHtklee KO mice we observed an increase in the number of writhes (41.25±11.36) versus WT (23.80±4.71), while in the tail immersion test no differences could be detected. Our results show that CRF/CRF1 receptors seem to be a protective role in latent pain sensitization induced by surgery and in the local inflammatory response to injury.

Effects of early surgical decompression on functional and histological outcomes after severe experimental thoracic spinal cord injury.

OBJECTIVE In acute traumatic brain injury, decompressive craniectomy is a common treatment that involves the removal of bone from the cranium to relieve intracranial pressure. The present study investigated whether neurological function following a severe spinal cord injury improves after utilizing either a durotomy to decompress the intradural space and/or a duraplasty to maintain proper flow of cerebrospinal fluid. METHODS Sixty-four adult female rats (n = 64) were randomly assigned to receive either a 3- or 5-level decompressive laminectomy (Groups A and B), laminectomy + durotomy (Groups C and D), or laminectomy + duraplasty with graft (Group E and F) at 24 hours following a severe thoracic contusion injury (200 kilodynes). Duraplasty involved the use of DuraSeal, a hydrogel dural sealant. Uninjured and injured control groups were included (Groups G, H). Hindlimb locomotor function was assessed by open field locomotor testing (BBB) and CatWalk gait analysis at 35 days postinjury. Bladder function was analyzed and bladder wall thickness was assessed histologically. At 35 days postinjury, mechanical and thermal allodynia were assessed by the Von Frey hair filament and hotplate paw withdrawal tests, respectively. Thereafter, the spinal cords were dissected, examined for gross anomalies at the injury site, and harvested for histological analyses to assess lesion volumes and white matter sparing. ANOVA was used for statistical analyses. RESULTS There was no significant improvement in motor function recovery in any treatment groups compared with injured controls. CatWalk gait analysis indicated a significant decrease in interlimb coordination in Groups B, C, and D (p < 0.05) and swing speed in Groups A, B, and D. Increased mechanical pain sensitivity was observed in Groups A, C, and F (p < 0.05). Rats in Group C also developed thermal pain hypersensitivity. Examination of spinal cords demonstrated increased lesion volumes in Groups C and F and increased white matter sparing in Group E (p < 0.05). The return of bladder automaticity was similar in all groups. Examination of the injury site during tissue harvest revealed that, in some instances, expansion of the hydrogel dural sealant caused compression of the spinal cord. CONCLUSIONS Surgical decompression provided no benefit in terms of neurological improvement in the setting of a severe thoracic spinal cord contusion injury in rats at 24 hours postinjury. Decompressive laminectomy and durotomy did not improve motor function recovery, and rats in both of these treatment modalities developed neuropathic pain. Performing a durotomy also led to increased lesion volumes. Placement of DuraSeal was shown to cause compression in some rats in the duraplasty treatment groups. Decompressive duraplasty of 3 levels does not affect functional outcomes after injury but did increase white matter sparing. Decompressive duraplasty of 5 levels led to neuropathic pain development and increased lesion volumes. Further comparison of dural repair techniques is necessary.

Central sensitization as a determinant of patients' benefit from total hip and knee replacement.

BACKGROUND: Discrepancies exist between osteoarthritic joint changes and pain severity before and after total hip (THR) and knee (TKR) replacement. This study investigated whether the interaction between pre-operative widespread hyperalgesia and severity of radiographic osteoarthritis (OA) was associated with pain severity before and after joint replacement. METHODS: Data were analysed from 232 patients receiving THR and 241 receiving TKR. Pain was assessed pre-operatively and at 12 months post-operatively using the WOMAC Pain Scale. Widespread hyperalgesia was assessed through forearm pressure pain thresholds (PPTs). Radiographic OA was evaluated using the Kellgren and Lawrence scheme. Statistical analysis was conducted using multilevel models, and adjusted for confounding variables. RESULTS: Pre-operative: In knee patients, there was weak evidence that the effect of PPTs on pain severity was greater in patients with more severe OA (Grade 3 OA: ß = 0.96 vs. Grade 4: ß = 4.03), indicating that in these patients higher PPTs (less widespread hyperalgesia) was associated with less severe pain. In hip patients, the effect of PPTs on pain did not differ with radiographic OA (Grade 3 OA: ß = 3.95 vs. Grade 4: ß = 3.67). Post-operative: There was weak evidence that knee patients with less severe OA who had greater widespread hyperalgesia benefitted less from surgery (Grade 3 OA: ß = 2.28; 95% CI -1.69 to 6.25). Conversely, there was weak evidence that hip patients with more severe OA who had greater widespread hyperalgesia benefitted more from surgery (Grade 4 OA: ß = -2.92; 95% CI -6.58 to 0.74). CONCLUSIONS: Widespread sensitization may be a determinant of how much patients benefit from joint replacement, but the effect varies by joint and severity of structural joint changes. SIGNIFICANCE: Pre-operative widespread hyperalgesia and radiographic osteoarthritis (OA) severity may influence how much patients benefit from joint replacement. Patients undergoing knee replacement with less severe OA and greater widespread hyperalgesia benefitted less from surgery than patients with less hyperalgesia. Patients undergoing hip replacement with more severe OA and greater widespread hyperalgesia benefitted more than patients with less hyperalgesia.

Localized Sympathectomy Reduces Mechanical Hypersensitivity by Restoring Normal Immune Homeostasis in Rat Models of Inflammatory Pain.

UNLABELLED: Some forms of chronic pain are maintained or enhanced by activity in the sympathetic nervous system (SNS), but attempts to model this have yielded conflicting findings. The SNS has both pro- and anti-inflammatory effects on immunity, confounding the interpretation of experiments using global sympathectomy methods. We performed a "microsympathectomy" by cutting the ipsilateral gray rami where they entered the spinal nerves near the L4 and L5 DRG. This led to profound sustained reductions in pain behaviors induced by local DRG inflammation (a rat model of low back pain) and by a peripheral paw inflammation model. Effects of microsympathectomy were evident within one day, making it unlikely that blocking sympathetic sprouting in the local DRGs or hindpaw was the sole mechanism. Prior microsympathectomy greatly reduced hyperexcitability of sensory neurons induced by local DRG inflammation observed 4 d later. Microsympathectomy reduced local inflammation and macrophage density in the affected tissues (as indicated by paw swelling and histochemical staining). Cytokine profiling in locally inflamed DRG showed increases in pro-inflammatory Type 1 cytokines and decreases in the Type 2 cytokines present at baseline, changes that were mitigated by microsympathectomy. Microsympathectomy was also effective in reducing established pain behaviors in the local DRG inflammation model. We conclude that the effect of sympathetic fibers in the L4/L5 gray rami in these models is pro-inflammatory. This raises the possibility that therapeutic interventions targeting gray rami might be useful in some chronic inflammatory pain conditions. SIGNIFICANCE STATEMENT: Sympathetic blockade is used for many pain conditions, but preclinical studies show both pro- and anti-nociceptive effects. The sympathetic nervous system also has both pro- and anti-inflammatory effects on immune tissues and cells. We examined effects of a very localized sympathectomy. By cutting the gray rami to the spinal nerves near the lumbar sensory ganglia, we avoided widespread sympathetic denervation. This procedure profoundly reduced mechanical pain behaviors induced by a back pain model and a model of peripheral inflammatory pain. One possible mechanism was reduction of inflammation in the sympathetically denervated regions. This raises the possibility that therapeutic interventions targeting gray rami might be useful in some inflammatory conditions.

Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity.

Decreased spinal cord GABAergic inhibition is a major contributor to the persistent neuropathic pain that can follow peripheral nerve injury. Recently, we reported that restoring spinal cord GABAergic signaling by intraspinal transplantation of cortical precursors of GABAergic interneurons from the embryonic medial ganglionic eminence (MGE) can reverse the mechanical hypersensitivity (allodynia) that characterizes a neuropathic pain model in the mouse. We show that MGE cell transplants are also effective against both the mechanical allodynia and the heat hyperalgesia produced in a paclitaxel-induced chemotherapy model of neuropathic pain. To test the necessity of GABA release by the transplants, we also studied the utility of transplanting MGE cells from mice with a deletion of VGAT, the vesicular GABA transporter. Transplants from these mice, in which GABA is synthesized but cannot be stored or released, had no effect on mechanical hypersensitivity or heat hyperalgesia in the paclitaxel model. Taken together, these results demonstrate the therapeutic potential of GABAergic precursor cell transplantation in diverse neuropathic pain models and support our contention that restoration of inhibitory controls through release of GABA from the transplants is their mode of action.

Comparative analysis of the influence of Fructus Ligustri Lucidi on a rat lumbar disc herniation model.

Lumbar disc herniation (LDH) is a term used for a group of conditions, including back pain, femoral nerve pain and sciatica. Currently available treatments and surgical options are insufficient for patients with LDH. Fructus Ligustri Lucidi (FLL) is a herb that is used for treating age-associated diseases. The results of the present study suggested that FLL may be used for treatment of patients with LDH. In the present study, matrix metalloproteinase-1, -3, -8 and -9 (MMP-1, -3, -8 and -9) protein and mRNA expression downregulation was observed in patients with LDH according to western blotting and reverse transcription-quantitative polymerase chain reaction. By contrast, upregulation of interleukin-2 (IL-2), IL-6, IL-8 and tumor necrosis factor-α (TNF-α) expression was observed in patients with LDH, according to an enzyme-linked immunosorbent assay. Mechanical allodynia was observed in rats with LDH not treated with FLL; however, not in FLL­treated rats. IL-2, IL-6, IL-8 and TNF-α expression levels in the serum from untreated rats were significantly higher than that of the FLL­treated rat models. Protein expression levels of MMPs in FLL-treated rats were lower than those in untreated rats. However, the mechanisms underlying the association between FLL and protein expression levels require further investigation.

Impact of surgical excision of lesions on pain in a rat model of endometriosis.

BACKGROUND: Chronic pain is the most common and disabling feature of endometriosis. Surgical excision of endometriosis lesions provides relief but pain relapse is common. Studies in a preclinical model of endometriosis might help to unravel the role of the ectopic lesions as the source of pain. Thus, we evaluated the impact of lesion excision on mechanical hyperalgesia in a preclinical model of endometriosis pain. METHODS: Endometriosis was induced by implanting autologous uterine tissue onto the gastrocnemius muscle. Surgical excision or aspiration drainage of the cystic lesion was performed at different times post-implant and mechanical nociceptive thresholds were assessed at the site of the lesion. RESULTS: Lesions at 2, 8 and 16 weeks post-implant produced mechanical hyperalgesia of similar magnitude (n = 6/group). Excision of lesions (n = 6/group) produced a longer inhibition, with a magnitude and time course depending upon the timing of excision. Excision at 2 and 8 weeks produced a rapid onset marked attenuation of hyperalgesia, which returned to pre-excision values by post-surgical week 3. In contrast, excision of the lesion at 16 weeks produced a peak of inhibition of hyperalgesia 2 weeks post-excision, but then the inhibition was sustained. Aspiration of fluid from cysts in the lesions briefly attenuated mechanical hyperalgesia (n = 6/group). CONCLUSIONS: In this preclinical model, we demonstrate that endometriosis pain is alleviated by surgical excision of the ectopic lesion or drainage of its cysts, providing support for the clinical observation that endometriosis pain is dependent upon the ongoing presence of the lesions.

Treatment principles for coccygodynia.

AIM: An evaluation of treatment methods and outcomes for coccygodynia cases that do not respond to conservative treatment. MATERIAL AND METHODS: Local anesthetic and steroid injections were applied in 32 coccygodynia cases that did not respond to conservative treatment (average of 15 months). Coccyx excision was performed as surgical treatment in 25 cases that had pain relief after the injections but later re-presented with complaints. The patients' pain levels were assessed with VAS. Postacchini classification was used for patient classification based on plain radiography. RESULTS: 20 (62%) of the cases (the total including injection and surgery groups) had a trauma history. Majority of the cases treated with local steroid injection included patients with Type I, while the 25 cases that received surgical treatment predominantly included Type II patients. One case had post-operative skin infection, which was treated with antibiotics. It was observed by comparing pre-operative and post-operative pain scores that both methods provided significant pain relief in all patients. CONCLUSION: While local steroid injection is an effective method of treatment for Type I patients, the coccyx removal is an effective method for controlling the pain in patients with trauma history and in Type II, III and IV patients.

Redistribution of voltage-gated sodium channels after nerve decompression contributes to relieve neuropathic pain in chronic constriction injury.

Nerve decompression is an important therapeutic strategy to relieve neuropathic pain and promote the peripheral nerve regeneration. To address these issues, we investigated the effects of nerve decompression on relief of neuropathic pain behaviors, redistribution of voltage-gated sodium channels (VGSCs), and skin reinnervation with chronic constriction injury (CCI). At post-operative week (POW) 4, animals were divided into a decompression group, in which the ligatures were removed, and a CCI group, in which the ligatures remained. Thermal hyperalgesia and mechanical allodynia at POW 8 had distinct reductions in decompression group compared to CCI group. At that time in CCI group, morphological evidence of pan VGSCs (Pan Nav) and isoforms of VGSCs (Nav1.6, Nav1.9, except for Nav1.8) were shown the widely distribution along the injured sciatic nerve. All of the VGSCs in decompression group became clustering around the node of Ranvier, similar to the pattern of control sciatic nerve at POW 8. Skin reinnervation was demonstrated by epidermal nerve density (END) for protein gene product 9.5 (PGP 9.5)-immunoreactive (IR) nerve fibers and a significant difference between groups only at POW 24 (p=0.01). Growth-associated protein 43 (GAP-43) is participated in the nerve fiber growth and sprouting, a difference in END for GAP-43-IR nerve fibers at POW 24 between groups were also significant (p=0.02). These observations demonstrated that nerve decompression was accompanied with the disappearance of neuropathic pain behaviors after CCI. Morphological studies provided the evidence that redistribution of VGSCs along the injured sciatic nerve but still with an incomplete skin reinnervation. These significant findings demonstrated a role of VGSCs in the pathogenesis of neuropathic pain, and gave an approaching in pharmacological basis of therapeutics.

Autologous fat grafting alleviates burn-induced neuropathic pain in rats.

BACKGROUND: The management of neuropathic pain after burn injury is a critical clinical issue. Autologous fat grafting has been shown to alleviate neuropathic pain in certain cases, but has not been shown to alleviate the pain associated with burn-induced scars. The authors assessed the effectiveness of autologous fat grafting for the management of pain in burn-induced scars. METHODS: One paw of the experimental rats received a third-degree burn using a heated metal block. Neuropathic pain in the affected paw was assessed based on behavioral responses to thermal and mechanical stimuli. A graft (0.4 ml of autologous fat or a sham graft) was administered by injection to the burn scar and sham-burned paw. The animals were killed 4 weeks after the fat graft treatments; Masson trichrome stain of hind-paw skin and expression of phosphorylated p38 and OX42 in the dorsal horns of the spinal cords were examined. RESULT: The third-degree burns were completely healed at 4 weeks. Burn-induced scarring caused mechanical allodynia and increased the expression of phosphorylated p38 and OX42 in spinal cord dorsal horn microglial cells. Autologous fat grafting significantly alleviated mechanical allodynia (p < 0.05), and immunohistochemistry showed that the expression of phosphorylated p38 and OX42 was significantly lower in spinal cord dorsal horn microglial cells 4 weeks after fat grafting (p < 0.05). CONCLUSIONS: Autologous fat grafting is used daily in clinical practice. It is an effective treatment for the relief of burn-induced mechanical allodynia in rats. Further investigation of the clinical use of autologous fat grafting in burn patients is warranted.

Cervical radiofrequency neurotomy reduces central hyperexcitability and improves neck movement in individuals with chronic whiplash.

OBJECTIVE: This study aims to determine if cervical medial branch radiofrequency neurotomy reduces psychophysical indicators of augmented central pain processing and improves motor function in individuals with chronic whiplash symptoms. DESIGN: Prospective observational study of consecutive patients with healthy control comparison. SETTING: Tertiary spinal intervention centre in Calgary, Alberta, Canada. SUBJECTS: Fifty-three individuals with chronic whiplash associated disorder symptoms (Grade 2); 30 healthy controls. METHODS: Measures were made at four time points: two prior to radiofrequency neurotomy, and 1- and 3-months post-radiofrequency neurotomy. Measures included: comprehensive quantitative sensory testing (including brachial plexus provocation test), nociceptive flexion reflex, and motor function (cervical range of movement, superficial neck flexor activity during the craniocervical flexion test). Self-report pain and disability measures were also collected. One-way repeated measures analysis of variance and Friedman's tests were performed to investigate the effect of time on the earlier measures. Differences between the whiplash and healthy control groups were investigated with two-tailed independent samples t-test or Mann-Whitney tests. RESULTS: Following cervical radiofrequency neurotomy, there were significant early (within 1 month) and sustained (3 months) improvements in pain, disability, local and widespread hyperalgesia to pressure and thermal stimuli, nociceptive flexor reflex threshold, and brachial plexus provocation test responses as well as increased neck range of motion (all P < 0.0001). A nonsignificant trend for reduced muscle activity with the craniocervical flexion test (P > 0.13) was measured. CONCLUSIONS: Attenuation of psychophysical measures of augmented central pain processing and improved cervical movement imply that these processes are maintained by peripheral nociceptive input.

Pulsed radiofrequency modulates pain regulatory gene expression along the nociceptive pathway.

BACKGROUND: Pulsed radiofrequency (PRF) therapy is a clinical treatment utilizing electromagnetic energy aimed to relieve neuropathic pain. This is the first study examining the modulated expression of pain regulatory genes following the induction of the spared nerve injury (SNI) pain model and subsequently treated with PRF therapy. OBJECTIVES: The present study investigated the behavioral efficacy of PRF therapy in rats exhibiting sciatic nerve injury and examined gene expression changes in the sciatic nerve, ipsilateral L5 dorsal root ganglia (DRG), and spinal cord. STUDY DESIGN: A randomized, experimental trial. SETTING: Department of Biological Sciences, Illinois State University and Department of Psychology, Illinois Wesleyan University. METHODS: An SNI model was used in male Sprague-Dawley rats (weight 260-310 g). A sham surgery was also performed as a control group. After 3 days development of the SNI model, an RF electrode was applied to the sciatic nerve proximal to the site of injury and stimulated for 3 minutes. The response to mechanical stimuli was assessed throughout the duration of the study. Furthermore, changes in gene expression along the nociceptive tract (sciatic nerve, DRG, and spinal cord) were assessed 24 hours post-PRF therapy. RESULTS: It was observed that the mechanical allodynia, induced by SNI model, was reversed to control values within 24 hours post-PRF therapy. Additionally, modulated expression of pain regulatory genes was observed after induction of the SNI model. Following PRF therapy, expression of many of these genes returned to control values (sham) in each of the tissues tested. Increased proinflammatory gene expression, such as TNF-α and IL-6, observed in the sciatic nerve (site of injury) in the SNI group was returned to baseline values following PRF therapy. Up-regulation of GABAB-R1, Na/K ATPase, and 5-HT3r as well as down regulation of TNF-α and IL-6 were also observed in the DRG in the SNI-PRF group relative to the SNI group. Up-regulation of Na/K ATPase and c-Fos was found in the spinal cord following PRF treatment relative to the SNI group. LIMITATIONS: Immediate changes in gene expression were observed at 24 hours to better determine the mechanism with no long-term data at this time. Protein expression was not assessed in addition to gene expression changes. CONCLUSION: These results indicate that the electromagnetic energy applied via PRF therapy influences the reversal of behavioral and molecular effects of hypersensitivity developed from a peripheral nerve injury.

Increased pain sensitivity but normal function of exercise induced analgesia in hip and knee osteoarthritis--treatment effects of neuromuscular exercise and total joint replacement.

OBJECTIVE: To assess exercise induced analgesia (EIA) and pain sensitivity in hip and knee osteoarthritis (OA) and to study the effects of neuromuscular exercise and surgery on these parameters. DESIGN: The dataset consisted of knee (n = 66) and hip (n = 47) OA patients assigned for total joint replacement at Lund University Hospital undergoing pre-operative neuromuscular exercise and 43 matched controls. Sensitivity to pressure pain was assessed by pressure algometry at 10 sites. Subjects were then instructed to perform a standardized static knee extension. Pressure pain thresholds (PPTs) were assessed at the contracting quadriceps muscle (Q) and at the resting deltoid muscle (D) before and during contraction. The relative increase in PPTs during contraction was taken as a measure of localized (Q) or generalized (D) EIA. Patients were assessed at baseline, following on average 12 weeks of neuromuscular exercise and 3 months following surgery. RESULTS: We found a normal function of EIA in OA patients at baseline. Previous studies have reported beneficial effects of physical exercise on pain modulation in healthy subjects. However, no treatment effects on EIA were seen in OA patients despite the increase in muscle strength following neuromuscular exercise and reduced pain following surgery. Compared to controls, OA patients had increased pain sensitivity and no beneficial effects on pain sensitivity were seen following treatment. CONCLUSIONS: To our knowledge, this is the first study of EIA in OA patients. Despite increased pain sensitivity, OA patients had a normal function of EIA.

Transplantation of NSCs with OECs alleviates neuropathic pain associated with NGF downregulation in rats following spinal cord injury.

Spinal cord injury (SCI) is a common and serious disease which often induces catastrophic consequence in patients. Part of them exhibit neuropathic pain which presents unique challenges to clinicians, and there is no effective approach for the treatment up to now. Neural stem cells (NSCs) transplantation, as a promising and an effective method, could be considered for the treatment of SCI, whereas a main problem is the low survival of NSCs in traumatic milieu in host spinal cords, and the effect of NSCs on sensory function remains elusive. In this study, we investigated the effect and underlying molecular mechanism of co-transplantation of NSCs with olfactory ensheathing cells (OECs) on sensory functional improvement. In the measurement of thermal and mechanical stimuli, NSCs grafts recovered sensory function in SCI rats, while OECs led to hyperalgesia, indicated by the tail flick latency (TFL) and paw withdraw latency (PWL) (p<0.05). Co-transplantation could promote NSCs survival, and reverses the hyperalgesia triggered by OECs. This was corresponding to a significant improvement in sensory function. Moreover, NGF expression was substantial downregulated in the spinal cord of co-transplantation rats. The present findings suggested that co-transplantation of NSCs with OECs could improve sensory function and the possible mechanism is involved in NGF downregulation in rats with SCI. This may give some new indications for the treatment of SCI in future clinic cell therapy trial.

Stress in the adult rat exacerbates muscle pain induced by early-life stress.

BACKGROUND: Early-life stress and exposure to stressful stimuli play a major role in the development of chronic widespread pain in adults. However, how they interact in chronic pain syndromes remains unclear. METHODS: Dams and neonatal litters were submitted to a restriction of nesting material (neonatal limited bedding [NLB]) for 1 week. As adults, these rats were exposed to a painless sound stress protocol. The involvement of sympathoadrenal catecholamines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) in nociception was evaluated through behavioral and enzyme-linked immunosorbent assays, surgical interventions, and intrathecal antisense treatments. RESULTS: Adult NLB rats exhibited mild muscle hyperalgesia, which was markedly aggravated by sound stress (peaking 15 days after exposure). Adrenal medullectomy did not modify hyperalgesia in NLB rats but prevented its aggravation by sound stress. Sustained administration of epinephrine to NLB rats mimicked sound stress effect. Intrathecal treatment with antisense directed to IL-6 receptor subunit gp130 (gp130), but not to tumor necrosis factor receptor type 1 (TNFR1), inhibited hyperalgesia in NLB rats. However, antisense against either gp130 or TNFR1 inhibited sound stress-induced enhancement of hyperalgesia. Compared with control rats, NLB rats exhibit increased plasma levels of IL-6 but decreased levels of TNFα, whereas sound stress increases IL-6 plasma levels in control rats but not in NLB rats. CONCLUSIONS: Early-life stress induces a persistent elevation of IL-6, hyperalgesia, and susceptibility to chronic muscle pain, which is unveiled by exposure to stress in adults. This probably depends on an interaction between adrenal catecholamines and proinflammatory cytokines acting at muscle nociceptor level.

Electroacupuncture and lumbar transplant of GDNF-secreting fibroblasts synergistically attenuate hyperalgesia after sciatic nerve constriction.

Electroacupuncture (EA) has been shown to induce potent analgesic effects on neuropathic pain in both patients and rodents. Cell therapy to release antinociceptive agents near the pain processing centers of the spinal cord is a promising next step in the development of treatment modalities. This study investigated the effects of the combination of EA and cell therapy by glial cell line-derived neurotrophic factor (GDNF) on neuropathic pain in rats. The hyperalgesic state was induced by chronic constriction injury (CCI) of the sciatic nerve and fibroblasts genetically modified to secrete bioactive GDNF (FBs-GDNF) were used for cell therapy. Fifty-eight rats with neuropathic pain were randomly divided into five groups (CCI+PBS, n = 11; CCI+FBs-GDNF, n = 12; CCI+EA+PBS, n = 11; CCI+EA+FBs-pLNCX2, n = 12; CCI+EA+FBs-GDNF, n = 12). On the 7th day after CCI, the rats received intrathecal transplantation of FBs-GDNF or control fibroblasts (FBs-pLNCX2). In the meantime, EA was administered once every other day from the 7th day after CCI surgery for 21 days. The paw withdrawal latency (PWL) to radiant heat was measured every other day. The results showed that the ipsilateral PWL of the rats from all three EA treatment groups significantly increased starting on the 12th day compared with the PBS control group. Strikingly, the group which received EA treatment and FBs-GDNF transplantation (CCI+EA+FBs-GDNF) showed a significantly decreased thermal hyperalgesia after 2 weeks post CCI surgery compared with the groups which received EA treatment and FBs-pLNCX2 transplantation (CCI+EA+FBs-pLNCX2) or PBS (CCI+EA+PBS) as well as the FBs-GDNF transplantation group without EA treatment (CCI+FBs-GDNF). Our data suggest that EA and cell therapy can synergistically attenuate hyperalgesia in neuropathic pain rats.

Transplantation of human umbilical cord blood or amniotic epithelial stem cells alleviates mechanical allodynia after spinal cord injury in rats.

Stem cell therapy is a potential treatment for spinal cord injury (SCI), and a variety of different stem cell types have been grafted into humans suffering from spinal cord trauma or into animal models of spinal injury. Although several studies have reported functional motor improvement after transplantation of stem cells into injured spinal cord, the benefit of these cells for treating SCI-induced neuropathic pain is not clear. In this study, we investigated the therapeutic effect of transplanting human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) or amniotic epithelial stem cells (hAESCs) on SCI-induced mechanical allodynia (MA) and thermal hyperalgesia (TH) in T13 spinal cord hemisected rats. Two weeks after SCI, hUCB-MSCs or hAESCs were transplanted around the spinal cord lesion site, and behavioral tests were performed to evaluate changes in SCI-induced MA and TH. Immunohistochemical and Western blot analyses were also performed to evaluate possible therapeutic effects on SCI-induced inflammation and the nociceptive-related phosphorylation of the NMDA NR1 receptor subunit. While transplantation of hUCB-MSCs showed a tendency to reduce MA, transplantation of hAESCs significantly reduced MA. Neither hUCB-MSC nor hAESC transplantation had any effect on SCI-induced TH. Transplantation of hAESCs also significantly reduced the SCI-induced increase in NMDA receptor NR1 subunit phosphorylation (pNR1) expression in the spinal cord. Both hUCB-MSCs and hAESCs reduced the SCI-induced increase in spinal cord expression of the microglial marker, F4/80, but not the increased expression of GFAP or iNOS. Taken together, these findings demonstrate that the transplantation of hAESCs into the injured spinal cord can suppress mechanical allodynia, and this effect seems to be closely associated with the modulation of spinal cord microglia activity and NR1 phosphorylation.