Increased GABA+ in People With Migraine, Headache, and Pain Conditions- A Potential Marker of Pain.

Treatment outcomes for migraine and other chronic headache and pain conditions typically demonstrate modest results. A greater understanding of underlying pain mechanisms may better inform treatments and improve outcomes. Increased GABA+ has been identified in recent studies of migraine, however, it is unclear if this is present in other headache, and pain conditions. We primarily investigated GABA+ levels in the posterior cingulate gyrus (PCG) of people with migraine, whiplash-headache and low back pain compared to age- and sex-matched controls, GABA+ levels in the anterior cingulate cortex (ACC) and thalamus formed secondary aims. Using a cross-sectional design, we studied people with migraine, whiplash-headache or low back pain (n = 56) and compared them with a pool of age- and sex-matched controls (n = 22). We used spectral-edited magnetic resonance spectroscopy at 3T (MEGA-PRESS) to determine levels of GABA+ in the PCG, ACC and thalamus. PCG GABA+ levels were significantly higher in people with migraine and low back pain compared with controls (eg, migraine 4.89 IU ± 0.62 vs controls 4.62 IU ± 0.38; P = .02). Higher GABA+ levels in the PCG were not unique to migraine and could reflect a mechanism of chronic pain in general. A better understanding of pain at a neurochemical level informs the development of treatments that target aberrant brain neurochemistry to improve patient outcomes. PERSPECTIVE: This study provides insights into the underlying mechanisms of chronic pain. Higher levels of GABA+ in the PCG may reflect an underlying mechanism of chronic headache and pain conditions. This knowledge may help improve patient outcomes through developing treatments that specifically address this aberrant brain neurochemistry.

Oxygen-Ozone Therapy in the Rehabilitation Field: State of the Art on Mechanisms of Action, Safety and Effectiveness in Patients with Musculoskeletal Disorders.

In recent years, the interest in oxygen-ozone (O2O3) therapy application has considerably increased in the field of rehabilitation. Despite its widespread use in common clinical practice, the biochemical effects of O2O3 are still far from being understood, although its chemical properties seem to play a pivotal role in exerting its positive effects on different pathological conditions. Indeed, the effectiveness of O2O3 therapy might be partly due to the moderate oxidative stress produced by O3 interactions with biological components. O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune over-activation, and most musculoskeletal disorders share these pathophysiological processes. The present comprehensive review depicts the state-of-the-art on the mechanisms of action, safety and effectiveness of O2O3 therapy in the complex scenario of the management of musculoskeletal disorders. Taken together, our findings suggest that O2O3 therapy seems to reduce pain and improve functioning in patients affected by low back pain and knee osteoarthritis, as reported by several studies in the literature. However, to date, further studies are warranted to clearly investigate the therapeutic effects of this promising therapy on other musculoskeletal disorders in the field of rehabilitation.

Endocannabinoids release after Osteopathic Manipulative Treatment. A brief review.

OBJECTIVES: Since 70's, scientific research has analyzed how many acute and chronic issues can affect body systems. In case of depression, chronic pain and overtraining, centrals and peripherals systems act to manage and maintain body adaptations. The aim of this study is to evaluate if the osteopathic treatment can increase the release of Cannabinoid receptor (CB) and promote the linkage with their receptors. CONTENT: Documents research is based on PubMed and Google Scholar databases. Keywords used were "osteopathic treatment", "manual therapy", "endocannabinoid", "beta endorphin (BE)", and " CB1" "massage". From 70 articles collected (published in the last 10 years) 52 were excluded as non-relevant to the study aim. SUMMARY: The Key points have been the similar results found by different authors during different treatment periods and with different doses. From 22 articles examined, 13 have established positive effects on CB increasing post osteopathic treatment, three articles have indicated the most targeted tissues in which the substances are most expressed, two articles indicate how physical activities produce antalgic effects by increasing CB's values. OUTLOOK: As a result of this review, osteopathic manipulation treatment seems to be a valid and effective instrument for the treatment of a series of pathologies such as chronic low back pain, fibromyalgia, spinal cord lesions, myofascial graft point, migraine, GI tract dysfunctions, and depression.

Low back pain in athletes can be controlled with acupuncture by a catecholaminergic pathway: clinical trial.

BACKGROUND: Activation of the sympathetic nervous system attenuates inflammation via catecholamines. Recent evidence has shown that electroacupuncture (EA) activates neuronal networks involved in the release of dopamine and norepinephrine that control systemic inflammation. In muscle, catecholamines are related to cyclic adenosine monophosphate (cAMP). This signaling molecule has been implicated in recovery from sustained contractile activity, which may induce muscular pain, such as that which occurs during low back pain (LBP). OBJECTIVE: Our aim was to evaluate the effects of EA used for the control of LBP on the activation of the sympathetic nervous system in a randomized controlled clinical trial in athletes. METHODS: Two groups of athletes with acute or chronic low back pain were studied. EA, sham EA and pharmacological treatment (diclofenac sodium) were evaluated. The outcome measures included a pain score represented by a visual analogue scale (VAS) and serum levels of catecholamines quantified by enzyme-linked immunosorbent assay. In addition, blood was collected into chilled heparin tubes, placed in 96-well cell culture plates and incubated with an equal volume of Roswell Park Memorial Institute (RPMI) medium, with lipopolysaccharide (LPS) alone or with catecholamines. Tumor necrosis factor (TNF)-α levels in the supernatants were analyzed. RESULTS: The results indicated that the initial pain ratings did not differ between the groups analyzed. EA induced epinephrine secretion but not norepinephrine or dopamine secretion. Although EA and pharmacological treatment did not differ in terms of pain relief, in vitro epinephrine and norepinephrine reduced TNF-α production in response to LPS stimuli. CONCLUSION: EA activates the sympathetic nervous system and induces the release of epinephrine, which could ameliorate inflammation and protect muscular tissue in addition to relieving pain.

Interleukin-8 as a therapeutic target for chronic low back pain: Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse model.

BACKGROUND: Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study. METHODS: Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs. The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array. FINDINGS: IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice. INTERPRETATION: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. FUND: Supported by NIH, MMF, CIHR and FRQS.

Duhuo Jisheng Decoction inhibits SDF-1-induced inflammation and matrix degradation in human degenerative nucleus pulposus cells in vitro through the CXCR4/NF-κB pathway.

Lower back pain (LBP) is the most common disease in orthopedic clinics world-wide. A classic Fangji of traditional Chinese medicine, Duhuo Jisheng Decoction (DHJSD), has been proven clinically effective for LBP but its therapeutic mechanisms remain unclear. We hypothesized that DHJSD might relieve LBP through inhibiting the exaggerated proinflammatory cytokines and extracellular matrix (ECM) degradation. Thus, we studied the effects of DHJSD on stromal cell-derived factor-1 (SDF-1)-induced inflammation and ECM degradation in human nucleus pulposus cells (hNPCs). The primary hNPCs were isolated from either degenerated human intervertebral disc (HID) of LBP patients or normal HID of lumbar vertebral fracture patients, and cultured in vitro. The cells were treated with SDF-1 (10 ng/mL) and subsequently with different concentrations (100-500 µg/mL) of DHJSD for 24 h, respectively. We found that application of DHJSD significantly antagonized the SDF-1-induced production of proinflammatory cytokines and reduction of aggrecan and type II collagen in the hNPCs. DHJSD also markedly reduced the SDF-1-induced increase of CXCR4 and p-p65 and inhibited the nuclear translocation of p65 in the hNPCs. DHJSD, CXCR4-siRNA, and NF-κB inhibitor (BAY11-7082) caused the same inhibition of exaggerated proinflammatory cytokines in the SDF-1-treated hNPCs. These results provided compelling evidence that DHJSD may inhibit the generation of proinflammatory mediators and ECM degradation of HID through an orchestrated targeting at multiple molecules in the SDF-1/CXCR4/NF-κB pathway, thus offered novel mechanistic insights into the clinical effectiveness of DHJSD on LBP.

Phototherapy suppresses inflammation in human nucleus pulposus cells for intervertebral disc degeneration.

The etiology of intervertebral disc (IVD) degeneration accompanied by low back pain (LBP) is largely unknown, and there are no curative therapies. Painful IVD degeneration is associated with infiltrated macrophage-mediated inflammatory response of human nucleus pulposus (NP) cells. The present study aimed to address the hypothesis that pro-inflammatory cytokines derived from macrophages lead to the altered molecular phenotype of human NP cells and to investigate the effects of phototherapy (630, 525, 465 nm with 16, 32, 64 J/cm2) on pain-related cytokine interleukin (IL)-6 and chemokine IL-8 under inflammatory conditions in human NP cells. Human NP cells were treated with soluble factors derived from macrophages in an inflammatory microenvironment, similar to that found in degenerative IVD. Human NP cells were also treated with phototherapy (630, 525, 465 nm with 16, 32, 64 J/cm2), and their cytokine and chemokine levels were detected. The soluble factors caused modulated expression of IL-6, IL-8, and matrix metalloproteinases (MMPs) at the gene and protein levels, causing a shift toward matrix catabolism through the expression of MMPs and increased pain-related factors via preferential activation of the nuclear factor-kappa B (NF-κB) p50 protein. Importantly, phototherapy attenuated the protein and gene expression of pain-related factor IL-6 at all doses and wavelengths. Interestingly, phototherapy also modulated the protein and gene expression of IL-8, which is responsible for the anabolic response, at a wavelength of 465 nm at all doses, in human NP cells. These findings suggested that phototherapy, at an optimal dose and wavelength, might be a useful therapeutic tool to treat IVD degeneration.

Immediate Effects of Core Stabilization Exercise on ß-Endorphin and Cortisol Levels Among Patients With Chronic Nonspecific Low Back Pain: A Randomized Crossover Design.

OBJECTIVE: The main objective of the study was to measure the levels of plasma ß-endorphin (PB) and plasma cortisol (PC) under lumbar core stabilization exercise (LCSE), placebo and control conditions in patients with chronic nonspecific low back pain. METHODS: Twenty-four participants with chronic nonspecific low back pain participated in a randomized, placebo-controlled, crossover design study. There were 3 experimental exercise conditions: control condition (positioning in crook lying and rest), placebo condition (passive cycling in crook lying using automatic cycler), and LCSE on a Pilates device tested with a 48-hour interval between sessions by concealed randomization. A blood sample was collected before and after the exercise conditions. Plasma ß-endorphin and PC were measured through enzyme-linked immunosorbent assay and electrochemiluminescence in a Cobas E411 auto analyzer. RESULTS: A significant difference in PB level was identified before and after the LCSE condition (P < .05), whereas no significant differences were noted in control and placebo exercise conditions. Also, the trend of elevation of PB under the LCSE was significantly different compared with the placebo and control conditions (P < .01). In contrast, the PC level remained unchanged in all 3 conditions. CONCLUSION: The findings of this study indicate that LCSE could possibly influence PB but not PC level among patients with chronic nonspecific low back pain. The mechanism of action of the pain-relieving effect of LCSE might be related to an endogenous opioid mechanism as part of its effects and might not be involved with a stress-induced analgesia mechanism.

Vitamin D supplementation attenuates oxidative stress in paraspinal skeletal muscles in patients with low back pain.

PURPOSE: The aim of the study was to evaluate markers of oxidative stress and vitamin D receptor in paraspinal muscles in low back pain patients with vitamin D deficiency, with normal level of vitamin D, and after 5 weeks of vitamin D supplementation. METHODS: Patients were divided into three groups: supplemented (SUP) with vitamin D, placebo with normal concentration of vitamin D (SUF), and the placebo group with vitamin D deficiency (DEF). The concentration of serum vitamin D was measured before and after the supplementation with vitamin D (3200 IU/ day for 5 weeks). Markers of lipid and protein peroxidation, the activity of antioxidant enzymes, and protein content of vitamin D receptor was determined in multifidus muscle of patients. RESULTS: Vitamin D supplementation increased serum level of 25(OH)D3 (p < 0.001). In paraspinal muscle level of 8-isoprostanes and protein carbonyls was higher in DEF group as compared to the SUP group (p < 0.05). Antioxidant enzyme activity and vitamin D receptor in paraspinal muscle altered between the groups with different serum vitamin D concentration. The cytosolic superoxide dismutase and glutathione peroxidase activities were significantly higher in DEF group as compared to the SUP group (p < 0.05). CONCLUSIONS: An attenuation of markers of free radical damage of lipids and proteins was observed in participants supplemented with Vitamin D. Antioxidant enzyme activities in skeletal muscle differ among patients with different serum vitamin D concentration. Monitoring oxidative stress and VDR protein content might be useful for future studies on the mechanism(s) of vitamin D action in muscle.

Neurochemical changes in patients with chronic low back pain detected by proton magnetic resonance spectroscopy: A systematic review.

BACKGROUND: Low back pain is a highly prevalent health problem around the world, affecting 50% to 85% of people at some point in life. The purpose of this systematic review is to summarize the previous proton magnetic resonance spectroscopy studies on brain chemical changes in patients with chronic low back pain (CLBP). METHODS: We identified relevant studies from a literature search of PubMed and EMBASE from 1980 to March 2016. Data extraction was performed on the subjects' characteristics, MRS methods, spectral analyses, cerebral metabolites and perceptual measurements. RESULTS: The review identified 9 studies that met the inclusion criteria, comprised of data on 135 CLBP subjects and 137 healthy controls. Seven of these studies reported statistically different neurochemical alterations in patients with CLBP. The results showed that compared to controls, CLBP patients showed reductions of 1) N-acetyl-aspartate (NAA) in the dorsolateral prefrontal cortex (DLPFC), right primary motor cortex, left somatosensory cortex (SSC), left anterior insula and anterior cingulate cortex (ACC); 2) glutamate in the ACC; 3) myo-inositol in the ACC and thalamus; 4) choline in the right SSC; and 5) glucose in the DLPFC. CONCLUSION: This review provides evidence for alterations in the biochemical profile of the brain in patients with CLBP, which suggests that biochemical changes may play a significant role in the development and pathophysiology of CLBP and shed light on the development of new treatments for CLBP.

Therapeutic effects of naringin on degenerative human nucleus pulposus cells for discogenic low back pain.

BACKGROUND: Over half the population of the world will suffer from moderate or severe low back pain (LBP) during their life span. Studies have shown that naringin, a major flavonoid in grapefruit and an active compound extracted from a Chinese herbal medicine (Rhizoma Drynariae) possesses many pharmacological effects. PURPOSE: The aim of this study was to evaluate the influence of naringin on the growth of degenerative human nucleus pulposus (NP) cells, and its repair effects on protein and gene expressions of the cells. STUDY DESIGN/SETTING: This was an in vitro investigation of the human NP cells isolated from degenerated intervertebral discs that were interacted with various concentrated of naringin. METHOD: This study was exempted by the institutional Human Subjects Committee-2, University of Kansas School of Medicine-Wichita. Degenerative human NP cells were isolated from intervertebral discs of patients with discogenic LBP and cultured at 37°C with 5% CO2. The proliferation of NP cells was determined following treatment with various concentrations of naringin. The protein expressions of tumor necrosis factor-α (TNF-α) and Bone morphogenetic protein 2 (BMP-2) were tested using enzyme-linked immunosorbent assay. Aggrecan and type II collagen levels were measured by immunohistological staining. Further examination of the gene expression of aggrecan, Sox6, and MMP3 was performed after intervention with naringin for 3 days. RESULTS: The human NP cells were successfully propagated in culture and stained positive with toluidine blue staining. Naringin effectively enhanced the cell proliferation at an optimal concentration of 20 µg/mL. Naringin treatment resulted in significant inhibition of TNF-α, but elevated protein expressions of BMP-2, collagen II, and aggrecan. Naringin also increased disc matrix gene activity including aggrecan and Sox6, and decreased the gene expression of MMP3. CONCLUSION: Naringin effectively promotes the proliferation of degenerative human NP cells and improves the recuperation of the cells from degeneration by increasing expression of aggrecan, BMP-2, and Sox6 while inhibiting the expression of TNF-α and MMP3. This study suggests that naringin may represent an alternative therapeutic agent for disc degeneration.

Organotypic Cultures of Intervertebral Disc Cells: Responses to Growth Factors and Signaling Pathways Involved.

Intervertebral disc (IVD) degeneration is strongly associated with low back pain, a major cause of disability worldwide. An in-depth understanding of IVD cell physiology is required for the design of novel regenerative therapies. Accordingly, aim of this work was the study of IVD cell responses to mitogenic growth factors in a three-dimensional (3D) organotypic milieu, comprising characteristic molecules of IVD's extracellular matrix. In particular, annulus fibrosus (AF) cells were cultured inside collagen type-I gels, while nucleus pulposus (NP) cells in chondroitin sulfate A (CSA) supplemented collagen gels, and the effects of Platelet-Derived Growth Factor (PDGF), basic Fibroblast Growth Factor (bFGF), and Insulin-Like Growth Factor-I (IGF-I) were assessed. All three growth factors stimulated DNA synthesis in both AF and NP 3D cell cultures, with potencies similar to those observed previously in monolayers. CSA supplementation inhibited basal DNA synthesis rates, without affecting the response to growth factors. ERK and Akt were found to be phosphorylated following growth factor stimulation. Blockade of these two signaling pathways using pharmacologic inhibitors significantly, though not completely, inhibited growth factor-induced DNA synthesis. The proposed culture systems may prove useful for further in vitro studies aiming at future interventions for IVD regeneration.

[Impact of huolong moxibustion on TNF-α and pain degree in the patients of discogenic low back pain].

OBJECTIVE: To discuss the impact of huolong moxibustion on pain degree in the patients of discogenic low back pain and the effect mechanism. METHODS: Sixty-five patients were randomized into an observation group (33 cases) and a control group (32 cases). In the observation group, huolong moxibustion was applied along the distribution of the Governor Vessel, once a day. In the control group, the routine traction combined with massage therapy was adopted, once a day. In the two groups, the treatment was given 6 times a week, at interval of 1 day. In 3 weeks of treatment, pain score and serum tumor necrosis factor α (TNF-α) level were compared with those before treatment in the two groups. RESULTS: Compared with those before treatment, pain score and TNF-α level were reduced significantly after treatment in the two groups (both P < 0.05). The results in the observation group were lower than those in the control group (pain score: 1.95 ± 0.61 vs 2.11 ± 0.61; TNF-α: (1.33 ± 0.30) nmol/L vs (1.55 ± 0.48) nmol/L, (both P < 0.05). CONCLUSION: Huolong moxibustion significantly alleviates pain in the patients of discogenic low back pain and its effect mechanism is possibly relevant with TNF-α reducing.

[Deep Oscillation: therapeutic-rehabilitative experiences with a new electrostatic device]. / Deep Oscillation®: esperienze terapeutico-riabilitative con un nuovo innovativo strumento ad azione elettrostatica.

AIM: Deep Oscillation® is an apparatus that produces low frequency electromagnetic radiations able to modulate immune reactions and, therefore, applicable to pain, tumour and inflammation treatments. The aim of this study is to evaluate how the Deep Oscillation® therapy works on conventional therapy resistant patients as the apparatus can be applied either to trauma derived fom surgical wounds or on sports post-traumatic oedema, low back pain and/or sciatalgic pain and cervicobrachial pain. METHODS: In the first part of the study, 34 cases of recent surgical wounds have been treated with Deep Oscillation® with 3 times a week visits for 20 minutes. In the same way 30 cases of sports post-traumatic oedema, 20 cases of low back pain and/or sciatalgic pain and 10 cases of cervicobrachial pain were treated. Among these patients, 15 cases had also undergone contemporaneous nonsteroidal anti-inflammatory drugs intravenous drip, electrolytes and vitamins to verify the probable synergetic efficacy of both treatments. RESULTS: The results confirm that in some cases the Deep Oscillation® treatment is effective since the first/third therapy up to the restitutio ad integrum. It has also been demonstrated that the maximum efficiency of the Deep Oscillation® and nonsteroidal anti-inflammatory drugs synergetic treatment is probably due to the electromagnetic radiations able to facilitate the pharmacological uptake. CONCLUSION: This study confirms the capacity of the electrostatic energy, released by Deep Oscillation®, to stimulate the patient's neurosensory system, raising his pain threshold and facilitating his pharmacological uptake and restoring his functional recovery more quickly.

Protocol for the Cognitive Interventions and Nutritional Supplements (CINS) trial: a randomized controlled multicenter trial of a brief intervention (BI) versus a BI plus cognitive behavioral treatment (CBT) versus nutritional supplements for patients with long-lasting muscle and back pain.

BACKGROUND: Brief intervention programs are clinically beneficial, and cost efficient treatments for low back pain, when offered at 8-12 weeks, compared with treatment as usual. However, about 30% of the patients do not return to work. The European Guidelines for treatment of chronic low back pain recommends Cognitive Behavioral Therapy (CBT), but conclude that further research is needed to evaluate the effectiveness of CBT for chronic low back pain. METHODS/DESIGN: The aim of the multicenter CINS trial (Cognitive Interventions and Nutritional Supplements) is to compare the effectiveness of 4 different interventions; Brief Intervention, Brief Intervention and CBT, Brief Intervention and nutritional supplements of seal oil, and Brief Intervention and nutritional supplements of soy oil. All participants will be randomly assigned to the interventions. The nutritional supplements will be tested in a double blind design. 400 patients will be recruited from a population of chronic low back pain patients that have been sick listed for 2-10 months. Four outpatient clinics, located in different parts of Norway, will participate in recruitment and treatment of the patients.The Brief Intervention is a one session cognitive, clinical examination program based on a non-injury model, where return to normal activity and work is the main goal, and is followed by two booster sessions. The CBT is a tailored treatment involving 7 sessions, following a detailed manual. The nutritional supplements consist of a dosage of 10 grams of either soy or seal oil (capsules) per day for 3 months, administered in a double blind design. All patients will be followed up with questionnaires after 3, 6 and 12 months, while sick leave data will be collected up to at least 24 months after randomization. The primary outcome of the study is sick leave and will be based on register data from the National Insurance Administration. Secondary outcomes include self-reported data on disability, pain, and psychological variables. CONCLUSIONS: To our knowledge, the CINS trial will be the largest, randomized trial of psychological and nutritional interventions for chronic low back pain patients to date. It will provide important information regarding the effectiveness of CBT and seal oil for chronic low back pain patients. TRIAL REGISTRATION: http://www.clinicaltrials.gov, with registration number NCT00463970.

In vivo measurement of facet joint nitric oxide in patients with chronic low back pain.

STUDY DESIGN: Prospective case-control study testing a new diagnostic method. OBJECTIVE: The aim of the present study was to investigate the concentration of nitric oxide (NO) in the perifacetal region in patients with chronic low back pain and healthy controls. SUMMARY OF BACKGROUND DATA: Facet joint arthrosis may be a pain source in chronic back pain. Increased concentrations of NO, an oxygen-free radical, have been demonstrated in temporomandibular and knee joints with osteoarthritis. PATIENTS AND METHODS: Patients with at least 6 months' duration of chronic low back pain and signs of facet joint osteoarthrosis (n = 24) and healthy volunteers (n = 7) were included. A detailed questionnaire, including visual analogue scale, was completed before and 6 weeks after the measurements. NO was measured with a custom-designed electrochemical real-time NO sensor inserted under fluoroscopic guidance. All patients received corticosteroids and local anesthetics after NO measurements. RESULTS: NO measurements were obtained from all participants. No adverse effects were noted. The patients with chronic low back pain demonstrated higher concentrations of NO in the perifacetal region compared with healthy controls (1.66 +/- 0.28 vs. 0.46 +/- 0.14 nmol/L, P = 0.007). No association between NO concentration and pain duration or pain level was detected. Patients with a positive response to local anesthetics and corticosteroid injection (defined as a >or=20 mm reduction of visual analogue scale at the 6-week follow-up visit) had higher NO concentrations than patients without positive response. CONCLUSIONS: The study demonstrates that it is feasible and safe to measure NO with a real time-sensor in or around the facet joints. The findings of higher concentrations of NO in the perifacetal region in chronic low back patients compared with healthy controls indicate that the degenerative process of the joints in these patients may cause increased NO production. The observation of higher NO concentrations in the perifacetal region in patients responding to corticosteroid/local anesthetic infiltration indirectly suggest a more pronounced inflammatory process in these patients.

Magnetic resonance spectroscopy detects biochemical changes in the brain associated with chronic low back pain: a preliminary report.

Magnetic resonance (MR) spectroscopy is a noninvasive technique that can be used to detect and measure the concentration of metabolites and neurotransmitters in the brain and other organs. We used in vivo (1)H MR spectroscopy in subjects with low back pain compared with control subjects to detect alterations in biochemistry in three brain regions associated with pain processing. A pattern recognition approach was used to determine whether it was possible to discriminate accurately subjects with low back pain from control subjects based on MR spectroscopy. MR spectra were obtained from the prefrontal cortex, anterior cingulate cortex, and thalamus of 32 subjects with low back pain and 33 control subjects without pain. Spectra were analyzed and compared between groups using a pattern recognition method (Statistical Classification Strategy). Using this approach, it was possible to discriminate between subjects with low back pain and control subjects with accuracies of 100%, 99%, and 97% using spectra obtained from the anterior cingulate cortex, thalamus, and prefrontal cortex, respectively. These results demonstrate that MR spectroscopy, in combination with an appropriate pattern recognition approach, is able to detect brain biochemical changes associated with chronic pain with a high degree of accuracy.

Involvement of the cannabimimetic compound, N-palmitoyl-ethanolamine, in inflammatory and neuropathic conditions: review of the available pre-clinical data, and first human studies.

The endogenous cannabimimetic compound, and anandamide analogue, N-palmitoyl-ethanolamine (PEA), was shown to exert potent anti-inflammatory and analgesic effects in experimental models of visceral, neuropathic and inflammatory pain by acting via several possible mechanisms. However, only scant data have been reported on the regulation of PEA levels during pathological conditions in animals or, particularly, humans. We review the current literature on PEA and report the results of three separate studies indicating that its concentrations are significantly increased during three different inflammatory and neuropathic conditions, two of which have been assessed in humans, and one in a mouse model. In patients affected with chronic low back pain, blood PEA levels were not significantly different from those of healthy volunteers, but were significantly and differentially increased (1.6-fold, P<0.01, N=10 per group) 30 min following an osteopathic manipulative treatment. In the second study, the paw skin levels of PEA in mice with streptozotocin-induced diabetic neuropathic pain were found to be significantly higher (1.5-fold, P<0.005, N=5) than those of control mice. In the third study, colonic PEA levels in biopsies from patients with ulcerative colitis were found to be 1.8-fold higher (P<0.05, N=8-10) than those in healthy subjects. These heterogeneous data, together with previous findings reviewed here, substantiate the hypothesis that PEA is an endogenous mediator whose levels are increased following neuroinflammatory or neuropathic conditions in both animals and humans, possibly to exert a local anti-inflammatory and analgesic action.

Brain chemistry reflects dual states of pain and anxiety in chronic low back pain.

The neurobiology of the interaction between pain and anxiety is unknown. The present study examined interrelationships between: regional brain chemistry (as identified by in vivo proton magnetic resonance spectroscopy [(1)H-MRS] in dorsolateral prefrontal cortex [DLPFC], orbitofrontal cortex [OFC], cingulate and thalamus), pain (as measured by short form of the McGill Pain Questionnaire [SF-MPQ]), and anxiety (measured by the State-Trait Anxiety Inventory) in chronic low back pain (CLBP) patients, and contrasted to the relationship between brain chemistry and anxiety in sex and age-matched normal subjects. The results show that brain chemistry depends on a 3-way interaction of brain regions examined, subject groups (normal vs. CLBP), and anxiety levels (high vs. low). The concentration of N-Acetyl aspartate (the largest peak in (1)H-MRS) in OFC could distinguish between anxiety levels and between subject groups. Chemical-perceptual relationships were analyzed by calculating correlations between regional chemicals and perceptual measures of pain and anxiety. To isolate pain from anxiety, these maps were subdivided based on anxiety and, in the CLBP patients along anxiety-more-related vs. anxiety-less-related pain descriptors and along sensory vs. affective pain descriptors. There was a precise relationship between perception and brain chemistry. The chemical-perceptual network best related to pain in CLBP patients was comprised of the DLPFC and OFC; the chemical-anxiety network was best related to the OFC chemistry in normals and to all four regions studied in CLBP patients; and the cingulate was best related to the affective component of pain. We conclude that the chemical-perceptual mapping differentiates between closely related perceptual states of pain and anxiety in chronic pain and provides a brain regional-chemical-perceptual description of the long-term reorganization that occurs with chronic pain.

Endogenous opioid effects on motoneuron pool excitability: potential analgesic effect of acute exercise.

BACKGROUND: Metabolic and thermal stresses of exercise mediate the release of endogenous opioids depressing motoneuron activation (MNA). Although exercise is routinely presented as a coequal treatment for management of acute and chronic low back pain (LBP), it is not clear that exercise-induced endogenous opioid release can play a role in the analgesic and treatment outcomes for patients with LBP. Furthermore, if opioid involvement is present, it is not clear what level of exercise might be beneficial in the suppression of MNA and possibly LBP. OBJECTIVE: To determine whether exercise-induced endogenous opioid release can play a role in the analgesic and treatment outcomes for patients with LBP and to determine what level of exercise might be beneficial in the suppression of MNA and possibly LBP. METHODS: To test this hypothesis, male (n = 3) and female (n = 3) healthy volunteers were tested 6 times over a 4-week period. The 6 trials included high-intensity treadmill exercise at 75% O(2max) with placebo or naloxone, low-intensity exercise at 40% O(2max) (placebo or naloxone) and no exercise control (placebo or naloxone). The evoked spinal Hoffmann H-reflex (soleus muscle) was measured as the criterion for MNA before and after exercise and expressed with the maximal M-wave as the maximal H(max)/M(max) percent ratio. Naloxone (10 mg) or isovolumic saline solution was administered double-blind (1 mL bolus) after recovery from exercise and before H-reflex measurement. RESULTS: The results show a significant reduction in the H(max)/M(max) percent ratio for both exercise conditions (40.0 +/- 7.1 to 33.9 +/- 9.1% for 75% O(2max) and 37.4 +/- 4.8 to 33.0 +/- 5.3% for 40% O(2max); P <.01). Naloxone treatment did not attenuate the exercise-induced H(max)/M(max) percent ratio suppression. CONCLUSION: Endogenous opioids do not appear to modulate motoneuron responses to exercise under these experimental conditions.