Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors.

CONTEXT: Accumulating evidence has demonstrated that Toll-like receptors (TLRs), especially TLR4 localized on microglia/macrophages, may play a significant role in nociception. OBJECTIVE: We examine the role of TLR4 in a neuropathic pain model. Using behavioural/biochemical methods, we examined the influence of TLR4 antagonist on levels of hypersensitivity and nociceptive factors whose contribution to neuropathy development has been confirmed. MATERIALS AND METHODS: Behavioural (von Frey's/cold plate) tests were performed with Wistar male rats after intrathecal administration of a TLR4 antagonist (LPS-RS ULTRAPURE (LPS-RSU), 20 µG: lipopolysaccharide from Rhodobacter sphaeroides, InvivoGen, San Diego, CA) 16 H and 1 h before chronic constriction injury (cci) to the sciatic nerve and then daily for 7 d. three groups were used: an intact group and two cci-exposed groups that received vehicle or LPS-RSU. tissue [spinal cord/dorsal root ganglia (DRG)] for western blot analysis was collected on day 7. RESULTS: The pharmacological blockade of TLR4 diminished mechanical (from ca. 40% to 16% that in the INTACT group) and thermal (from ca. 51% to 32% that in the INTACT group) hypersensitivity despite the enhanced activation of IBA-1-positive cells in DRG. Moreover, LPS-RSU changed the ratio between IL-18/IL-18BP and MMP-9/TIMP-1 in favour of the increase of antinociceptive factors IL-18BP (25%-spinal; 96%-DRG) and TIMP-1 (15%-spinal; 50%-DRG) and additionally led to an increased IL-6 (40%-spinal; 161%-DRG), which is known to have analgesic properties in neuropathy. CONCLUSIONS: Our results provide evidence that LPS-RSU influences pain through the expression of TLR4. TLR4 blockade has analgesic properties and restores the balance between nociceptive factors, which indicates its engagement in neuropathy development.

Exercise Combined With Ultrasound Attenuates Neuropathic Pain in Rats Associated With Downregulation of IL-6 and TNF-α, but With Upregulation of IL-10.

BACKGROUND: Although there are several evidences that suggest efficacies of therapeutic ultrasound (TU) or treadmill exercise (TE) to alleviate nerve injury-associated pain, molecular mechanisms are less clear. We aimed to investigate the impact of TU and/or TE on neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve and their roles of proinflammatory and anti-inflammatory cytokines. METHODS: Rats were randomly divided into (n = 10 per group) sham operation (sham), CCI procedure followed by false application of TU (CCI + TU0), CCI procedure followed by false application of TU and TE (CCI + TU0 + TE), CCI, and CCI procedure followed by TU alone (CCI + TU), TE alone (CCI + TE), or both TU and TE (CCI + TU + TE) groups. TU and TE were administered daily, starting on postoperative day 8 (POD 8) for 3 weeks. Mechanical and thermal hypersensitivity, tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and IL-6 in the sciatic nerve were assessed on PODs 14 and 28. Data were analyzed by 1-way, 2-way, or 3-way analysis of variance of repeated measures or 1-way analysis of variance. RESULTS: After the interventions, there was statistical significance (all P ≤ .0001) between the groups for all outcome parameters, all in favor of the experimental group: 4.2 for mean mechanical withdrawal thresholds (95% confidence interval, 1.8-7.6) and 4.8 for mean thermal withdrawal latencies (95% confidence interval, 2.2-8.1). TU and/or TE provoked an increase in mechanical withdrawal thresholds and thermal withdrawal latencies in CCI rats. TU + TE was more effective to reverse pain hypersensitivity than having each treatment alone. On PODs 14 and 28, the CCI rats exhibited an upregulation of sciatic TNF-α and IL-6 expression, whereas TU or TE alone or TU + TE combination prevented the upregulation. TU and/or TE also showed the upregulation of less IL-10 expression in the sciatic nerve. CONCLUSIONS: We found that TU + TE is better than TU or TE alone for treating neuropathic pain. TU and/or TE for pain management may be straightly associated with less TNF-α and IL-6 expression and more IL-10 expression.

Pain location matters: the impact of leg pain on health care use, work disability and quality of life in patients with low back pain.

PURPOSE: In low back pain (LBP) patients, those with radiating leg pain or sciatica have poorer pain and disability outcomes. Few studies have assessed the effect of leg pain on health care use and quality of life. METHODS: Prospective cohort study of 1,581 UK LBP primary care consulters. Back pain, employment, health care utilisation, and quality of life (EQ-5D) data were collected at baseline, 6 and 12 months. At baseline, patients were classified as reporting (1) LBP only, (2) LBP and leg pain above the knee only (LBP + AK) or (3) LBP and leg pain extending below the knee (LBP + BK). RESULTS: Self-reported leg pain was common; at baseline 645 (41 %) reported LBP only, 392 (25 %) reported LBP + AK and 544 (34 %) reported LBP + BK. Patients with LBP + BK, compared to those with LBP only, were significantly more likely to be unemployed, take time off work, consult their family doctor, receive physical therapy, or be referred to other health care practitioners. There were statistically significant decrements in EQ-5D scores for LBP + AK compared to LBP only, and for LBP + BK compared to LBP + AK (p ≤ 0.05 for all comparisons). CONCLUSIONS: Patients with self-reported leg pain below the knee utilise more health care are more likely to be unemployed and have poorer quality of life than those with LBP only 12 months following primary care consultation. The presence of leg pain warrants early identification in primary care to explore if targeted interventions can reduce the impact and consequences of leg pain.

Psychological defensive profile of sciatica patients with neuropathic pain and its relationship to quality of life.

AIM: To identify differences between defense styles and mechanisms in sciatica patients with or without neuropathic pain and their relationship to quality of life. STUDY DESIGN: The study included 37 sciatica patients with neuropathic pain (SNP), 36 sciatica patients without neuropathic pain and 38 healthy subjects. Pain severity was measured using the Visual Analogue Scale (VAS). Psychological condition was assessed using the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI). Defense mechanisms were assessed using a 40-item Defense Style Questionnaire (DSQ-40) and quality of life was assessed using Short Form-36 (SF-36). RESULTS: BDI and BAI scores were significantly higher in the SNP group (p < 0.001). Idealization and immature defense styles, as well as isolation, displacement and somatization were significantly higher in the SNP group (p < 0.05). SF-36 parameters also differed significantly between the groups, with controls having the best scores and the SNP group the worst. In linear regression analysis, acting out and BDI were found to affect the pain domain of the SF-36 (p < 0.001). CONCLUSION: The acting out defensive style and BDI were independently associated with pain-related quality of life. In the SNP group, significant differences were found in the immature and neurotic styles of the defense mechanisms.

Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling.

Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: (1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and (2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1(-/-) mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive symptoms in a time dependent manner and was associated with profound hippocampal alterations such as impaired neurogenesis, reduced expression of neuroplasticity markers and myelin proteins. The onset of depressive-like behavior also coincided with increased hippocampal levels of TNF, and decreased expression of TNF receptor 2 (TNFR2), which were all fully restored after mice spontaneously recovered from pain. Notably, TNFR1(-/-) mice did not develop depressive-like symptoms after injury, nor were there changes in hippocampal neurogenesis and plasticity. Our data show that neuropathic pain induces a cluster of depressive-like symptoms and profound hippocampal plasticity that are dependent on TNF signaling through TNFR1.

Associations of socioeconomic and lifestyle characteristics, psychological symptoms, multimorbidity, and multisite pain with sciatica - a 15-year longitudinal study.

BACKGROUND CONTEXT: Sciatica is defined as pain radiating from the low back to the leg, usually below the knee. It is a disabling condition that causes a major burden to health care and society. Previous evidence of the multifactorial etiology of sciatica comes mostly from cross-sectional studies. Larger, longitudinal studies with a multidimensional set of variables are needed. PURPOSE: To examine how socioeconomic and lifestyle characteristics, psychological symptoms, multimorbidity, and multisite pain are associated with sciatica. STUDY DESIGN: A longitudinal study of the Northern Finland Birth Cohort 1966. PATIENT SAMPLE: In total 6,683 working-aged members of the Northern Finland Birth Cohort 1966. OUTCOME MEASURES: Self-reported sciatic pain status over a 15-year study period. METHODS: We conducted a 15-year longitudinal study from the age of 31 to 46. We used multivariable generalized estimation equations analysis to examine how socioeconomic characteristics (low education, unemployment, and living alone), lifestyle characteristics (overweight, obesity, current smoking, and physical inactivity), psychological symptoms (depression, anxiety), multimorbidity, and multisite pain were associated with sciatica. RESULTS: At the age of 31, 21.1% of the study population reported sciatic pain and at the age of 46, 36.7%. Multisite pain was clearly the strongest factor associated with sciatica (odds ratio [OR] 2.61, 95% confidence interval [CI] 2.34‒2.92). In descending order of effect size, older age, low education, psychological symptoms, multimorbidity, overweight, obesity, physical inactivity and current smoking were positively associated with sciatica. Their ORs varied between 1.17 and 2.18. Living alone was negatively associated with sciatica (OR 0.81, 95% CI 0.72‒0.90). CONCLUSIONS: Multisite pain had the strongest association with sciatica. The effect sizes of the other factors were clearly smaller. To our knowledge this is the first study to evaluate the association of multisite pain with sciatica. This finding may have considerable implications for clinical work treating patients with sciatica.

Intrathecal ultra-low dose naloxone enhances the antihyperalgesic effects of morphine and attenuates tumor necrosis factor-α and tumor necrosis factor-α receptor 1 expression in the dorsal horn of rats with partial sciatic nerve transection.

BACKGROUND: Glutamate homeostasis and microglia activation play an important role in the development and maintenance of neuropathic pain. We designed this investigation to examine whether ultra-low dose naloxone administered alone or in combination with morphine could alter the concentration of the excitatory amino acids (EAAs) glutamate and aspartate, as well as the expression of tumor necrosis factor-α (TNF-α) and its receptors (TNFR1 and TNFR2) in the spinal cord dorsal horn of rats with partial sciatic nerve transection (PST). METHODS: Male Wistar rats underwent intrathecal catheter implantation for drug delivery and were divided in 7 groups: sham-operated + saline (sham), PST + saline (S), PST + 15 ng naloxone (n), PST + 15 µg naloxone (N), PST + 10 µg morphine (M), PST + 15 ng naloxone + 10 µg morphine (Mn), PST + 15 µg naloxone + 10 µg morphine (MN). Thermal withdrawal latency and mechanical withdrawal threshold, TNF-α and TNFR expression in the spinal cord and dorsal root ganglia, and EAAs glutamate and aspartate concentration in cerebrospinal fluid dialysates were measured. RESULTS: Ten days after PST, rats developed hyperalgesia (P < 0.0001) and allodynia (P < 0.0001), and increased TNF-α (P < 0.0001) and TNFR1 expression (P = 0.0009) were measured in the ipsilateral spinal cord dorsal horn. The antihyperalgesic and antiallodynic effects of morphine (10 µg) were abolished by high-dose naloxone (15 µg; P = 0.0031) but enhanced by ultra-low dose naloxone (15 ng; P = 0.0015), and this was associated with a reduction of TNF-α (P < 0.0001) and TNFR1 (P = 0.0009) expression in the spinal cord dorsal horn and EAAs concentration (glutamate: P = 0.0001; aspartate: P = 0.004) in cerebrospinal fluid dialysate. Analysis of variance (ANOVA) or Student t test with Bonferroni correction were used for statistical analysis. CONCLUSIONS: Ultra-low dose naloxone enhances the antihyperalgesia and antiallodynia effects of morphine in PST rats, possibly by reducing TNF-α and TNFR1 expression, and EAAs concentrations in the spinal dorsal horn. Ultra-low dose naloxone may be a useful adjuvant for increasing the analgesic effect of morphine in neuropathic pain conditions.

The bothersomeness of sciatica: patients' self-report of paresthesia, weakness and leg pain.

The objective of the study was to investigate how patients with sciatica due to disc herniation rate the bothersomeness of paresthesia and weakness as compared to leg pain, and how these symptoms are associated with socio-demographic and clinical characteristics. A cross-sectional study was conducted on 411 patients with clinical signs of radiculopathy. Items from the Sciatica Bothersomeness Index (0 = none to 6 = extremely) were used to establish values for paresthesia, weakness and leg pain. Associations with socio-demographic and clinical variables were analyzed by multiple linear regression. Mean scores (SD) were 4.5 (1.5) for leg pain, 3.4 (1.8) for paresthesia and 2.6 (2.0) for weakness. Women reported higher levels of bothersomeness for all three symptoms with mean scores approximately 10% higher than men. In the multivariate models, more severe symptoms were associated with lower physical function and higher emotional distress. Muscular paresis explained 19% of the variability in self-reported weakness, sensory findings explained 10% of the variability in paresthesia, and straight leg raising test explained 9% of the variability in leg pain. In addition to leg pain, paresthesia and weakness should be assessed when measuring symptom severity in sciatica.

Evidence for lack of direct causality between pain and affective disturbances in a rat peripheral neuropathy model.

Chronic pain is frequently accompanied by the manifestation of emotional disturbances and cognitive deficits. While a causality relation between pain and emotional/cognitive disturbances is generally assumed, several observations suggest a temporal dissociation and independent mechanisms. We therefore studied Sprague-Dawley rats that presented a natural resistance to pain manifestation in a neuropathy model (spared nerve injury [SNI]) and compared their performance in a battery of behavioral paradigms-anxiety, depression and fear memory-with animals that presented a pain phenotype. Afterward, we performed an extensive volumetric analysis across prefrontal, orbitofrontal and insular cortical areas. The majority of SNI animals manifested mechanical allodynia (low threshold [LT]), but 13% were similar to Sham controls (high threshold [HT]). Readouts of spontaneous hypersensivity (paw flinches) were also significantly reduced in HT and correlated with allodynia. To increase the specificity of our findings, we segregated the SNI animals in those with left (SNI-L) and right (SNI-R) lesions and the lack of association between pain and behavior still remains. Left-lesioned animals, independent of the LT or HT phenotype, presented increased anxiety-like behaviors and decreased well-being. In contrast, we found that the insular cortex (agranular division) was significantly smaller in HT than in LT. To conclude, pain and emotional disturbances observed following nerve injury are to some extent segregated phenomena. Also, HT and LT SNI presented differences in insular volumes, an area vastly implicated in pain perception, suggesting a supraspinal involvement in the manifestation of these phenotypes.

Effect and neurophysiological mechanism of acupuncture in patients with chronic sciatica: protocol for a randomized, patient-assessor blind, sham-controlled clinical trial.

BACKGROUND: Sciatica is a relatively frequent illness that easily becomes a chronic and relapsing condition. Although numerous systematic reviews have analyzed various therapies for sciatica, the validity of their included studies is limited. Considering the limitations of conventional treatment options for sciatica, acupuncture is a possible option; however, evidence supporting its efficacy and mechanism in patients with sciatica is lacking. The aim of this proposed protocol is to investigate the effect and neurophysiological mechanism of acupuncture in patients with chronic sciatica. METHODS/DESIGN: This study is a randomized, patient-assessor blind, two-arm, parallel, non-penetrating, sham-controlled clinical trial. Eligible participants will include adults (aged 19-70 years old) with a clinical diagnosis of chronic sciatica (40 mm or more of a 100-mm visual analog scale (VAS) for bothersomeness) blinded to the treatment received. Patients will be randomly allocated into the acupuncture treatment group (manual acupuncture plus electroacupuncture (EA), n = 34) or the sham acupuncture control group (sham acupuncture plus placebo EA without electrical stimulation, n = 34). Groups will receive treatment twice a week for a total of eight sessions over 4 weeks. Functional magnetic resonance imaging will be implemented at baseline and endpoint to investigate the mechanism of acupuncture. The primary outcome measure is the VAS for bothersomeness and secondary outcomes include the VAS for pain intensity, Oswestry Disability Index, EuroQol 5-Dimension, Coping Strategy Questionnaire, Beck's Depression Inventory, and State-Trait Anxiety Inventory. Adverse events will be assessed at every visit. DISCUSSION: The results of this trial (which will be available in 2020) should provide important clinical evidence for the effect of acupuncture and demonstrate how acupuncture can be helpful for the treatment of chronic sciatica. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03350789 . Registered on 15 November 2017.

Kynurenic acid and zaprinast diminished CXCL17-evoked pain-related behaviour and enhanced morphine analgesia in a mouse neuropathic pain model.

BACKGROUND: The G protein-coupled receptor 35 (GPR35), is considered important for nociceptive transmission, as suggested by accumulating evidence. This receptor was discovered in 1998; however, a lack of pharmacological tools prevented a complete understanding of its function and how to exploit it therapeutically. We studied the influence of CXCL17, kynurenic acid and zaprinast on nociceptive transmission in naïve and neuropathic mice. Additionally, we investigated the influence of kynurenic acid and zaprinast on morphine effectiveness in neuropathic pain. METHODS: The chronic constriction injury (CCI) of the sciatic nerve in Swiss mice was performed. The CXCL17, kynurenic acid, zaprinast and morphine were injected intrathecally into naive and CCI-exposed mice at day 14. To evaluate tactile and thermal hypersensitivity, the von Frey and cold plate tests were used, respectively. RESULTS: Our results have shown, for the first time, that administration of CXCL17 in naïve mice induced strong pain-related behaviours, as measured by von Frey and cold plate tests. Moreover, we demonstrated that kynurenic acid and zaprinast diminished CXCL17-evoked pain-related behaviours in both tests. Kynurenic acid and zaprinast reduced thermal and tactile hypersensitivity developed by sciatic nerve injury and strongly enhanced the effectiveness of morphine in neuropathy. CONCLUSIONS: Our study highlights the importance of GPR35 as a receptor involved in neuropathic pain development. Therefore, these results suggest that the modulation of GPR35 could become a potential strategy for the treatment of neuropathic pain.

Direct evidence for the involvement of endogenous beta-endorphin in the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state.

Recent clinical studies have demonstrated that when opioids are used to control pain, psychological dependence is not a major problem. In this study, we further investigated the mechanisms that underlie the suppression of opioid reward under neuropathic pain in rodents. Sciatic nerve ligation suppressed a place preference induced by the selective mu-opioid receptor agonist [d-Ala(2), N-MePhe(4), Gly-ol(5)] enkephalin (DAMGO) and reduced both the increase in the level of extracellular dopamine by s.c. morphine in the nucleus accumbens and guanosine-5'-o-(3-[(35)S]thio) triphosphate ([(35)S]GTPgammaS) binding to membranes of the ventral tegmental area (VTA) induced by DAMGO. These effects were eliminated in mice that lacked the beta-endorphin gene. Furthermore, intra-VTA injection of a specific antibody to the endogenous mu-opioid peptide beta-endorphin reversed the suppression of the DAMGO-induced rewarding effect by sciatic nerve ligation in rats. These results provide molecular evidence that nerve injury results in the continuous release of endogenous beta-endorphin to cause the dysfunction of mu-opioid receptors in the VTA. This phenomenon could explain the mechanism that underlies the suppression of opioid reward under a neuropathic pain-like state.

Health status, symptoms and health counselling among middle-aged men: comparison of men at low and high risk.

AIM: To assess the levels of health indicators, health behaviour and health counselling among men at low and high risk for adverse health outcomes. METHODS: A total of 273 middle-aged men, 145 at low and 128 at high risk for adverse health outcomes, were studied. Two- and three-way tables with chi-squared tests were performed to identify differences between the groups. A step-wise logistic regression model was used to analyse symptoms and complaints associated with the likelihood of perceived health. RESULTS: One-half of the low-risk men were overweight, of whom 8% were obese. Forty per cent of the low-risk men smoked cigarettes and one-fifth used alcohol excessively. Headache, chest and back pain, stress, and insomnia occurred frequently (range: 20-38%) and were highly correlated with depression. Joint pain (p = 0.012) in the low-risk men and sciatica (p = 0.047) in the high-risk men were the only statistically significant differences related to normal weight vs. overweight status. There was a greater than sixfold odds of average/poor health among low-risk men who were depressed than in those who were not depressed men. Only a small percentage of the low-risk men had received counselling from professionals for different health issues, including weight control and smoking cessation; the corresponding percentages were somewhat higher when given by family members. CONCLUSIONS: A real need for better counselling was found among middle-aged men identified with obesity and risky behaviours. Public health nurses and other health workers should be aware of the differences between men at low and high risk. Men had different health experiences and lifestyles in these groups. More research is needed to determine the most efficient counselling strategies among men.

Biographical suspension and liminality of Self in accounts of severe sciatica.

Sciatica is a common form of low back pain (LBP) that has been identified as distinct both in terms of the persistence and severity of symptoms. Little research has explored individual experiences of sciatica, and none focuses on individuals with the most severe, long-lasting symptoms who may experience the most profound impact. This paper addresses this gap through proposing a theoretical framework for understanding such experiences, that of biographical suspension as a form of liminality of Self. Twenty semi-structured interviews were conducted with individuals with severe sciatic symptoms between January 2016‒March 2017, as part of the UK-based SCOPiC (SCiatica Outcomes in Primary Care) randomised controlled trial. Data were analysed thematically using the constant comparison method. The concept of 'biographical suspension', originally developed in LBP, emerged as one whereby individuals put life on-hold in the expectation of an eventual return to their former, pain-free selves. Deeper analysis extended this concept to a form of liminality, whereby individuals are caught between pre- and post-sickness selves, unable to fully identify with either. This liminality is underpinned by ongoing beliefs about sciatica as a temporary and fixable 'injury' rather than long-term 'illness', even among those with long-lasting symptoms. This led to a disjuncture between individuals' ongoing pain beliefs and experiences, resulting in longer-term psychological impacts. Biographical suspension is further conceptualised as an experiential stage giving rise to four distinct short-term trajectories: i) symptom resolution leading individuals to occupy a clearly post-liminal state; ii) remaining in suspended liminality; iii) ongoing symptoms leading to a post-liminal state of resignation; ix) a state of being both between sickness and wellness, and straddling hope and fear; thus exemplifying differing states of liminality experienced over time. Findings have implications for the support provided in clinical settings to individuals who may struggle to self-manage due to sustained liminality of Self.

A clinical genetic method to identify mechanisms by which pain causes depression and anxiety.

BACKGROUND: Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. RESULTS: We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood--the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. CONCLUSION: Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts.

Rat exposure in mice with neuropathic pain induces fear and antinociception that is not reversed by 5-HT2C receptor activation in the dorsal periaqueductal gray.

Previous studies have demonstrated that serotonin 5-HT2C receptors in the dorsal periaqueductal gray (dPAG) mediate both anxiety and antinociception in mice submitted to the elevated plus maze. The present study examined the effects of intra-dPAG infusion of the serotonin 5-HT2C receptor agonist (MK-212) in the defensive reactions and antinociception in mice with neurophatic pain confronted by a predator. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve, and predator confrontation was performed using the rat exposure test (RET). Our results demonstrated that both sham-operated and CCI mice exhibited intense defensive reactions when confronted by rats. However, rat-exposed CCI mice showed reduced pain reactivity in comparison to CCI mice exposed to a toy rat. Intra-dPAG infusion of MK-212 prior to predator exposure did not significantly alter defensive or antinociceptive responses. To our knowledge, our results represent the first evidence of RET-induced antinociception in mice. Moreover, the results of the present study suggest that 5-HT2C receptor activation in the dPAG is not critically involved in the control of predator-evoked fearful or antinociceptive responses.

Does Kinesiophobia Modify the Effects of Physical Therapy on Outcomes in Patients With Sciatica in Primary Care? Subgroup Analysis From a Randomized Controlled Trial.

BACKGROUND: A higher level of kinesiophobia appears to be associated with poor recovery in patients with sciatica. OBJECTIVE: The aim of this study was to investigate whether kinesiophobia modifies the effect of physical therapy on outcomes in patients with sciatica. DESIGN: This was a subgroup analysis from a randomized controlled trial. SETTING: The study was conducted in a primary care setting. PATIENTS: A total of 135 patients with acute sciatica participated. INTERVENTION: Patients were randomly assigned to groups that received (1) physical therapy plus general practitioners' care (intervention group) or (2) general practitioners' care alone (control group). MEASUREMENTS: Kinesiophobia at baseline was measured with the Tampa Scale for Kinesiophobia (TSK) and a single substitute question for kinesiophobia (SQK). Pain and recovery were assessed at 3- and 12-month follow-ups. Regression analysis was used to test for interaction between the level of kinesiophobia at baseline and treatment allocation. Subgroup results were calculated for patients classified with high fear of movement and for those classified with low fear of movement. RESULTS: Kinesiophobia at baseline interacted with physical therapy in the analysis with leg pain intensity at 12-month follow-up. Kinesiophobia at baseline did not interact with physical therapy regarding any outcome at 3-month follow-up or recovery at 12-month follow-up. When comparing both treatment groups in the subgroup of patients with high fear of movement (n=73), the only significant result was found for leg pain intensity difference from baseline at 12-month follow-up (intervention group: X̅=-5.0, SD=2.6; control group: X̅=-3.6, SD=2.7). LIMITATIONS: The post hoc study design and relatively small sample size were limitations of the study. CONCLUSIONS: In 135 patients with sciatica, evidence shows that patients with a higher level of kinesiophobia at baseline may particularly benefit from physical therapy with regard to decreasing leg pain intensity at 12-month follow-up.

A Fear-Avoidance Beliefs Questionnaire (FABQ) and the role of fear-avoidance beliefs in chronic low back pain and disability.

Pilot studies and a literature review suggested that fear-avoidance beliefs about physical activity and work might form specific cognitions intervening between low back pain and disability. A Fear-Avoidance Beliefs Questionnaire (FABQ) was developed, based on theories of fear and avoidance behaviour and focussed specifically on patients' beliefs about how physical activity and work affected their low back pain. Test-retest reproducibility in 26 patients was high. Principal-components analysis of the questionnaire in 210 patients identified 2 factors: fear-avoidance beliefs about work and fear-avoidance beliefs about physical activity with internal consistency (alpha) of 0.88 and 0.77 and accounting for 43.7% and 16.5% of the total variance, respectively. Regression analysis in 184 patients showed that fear-avoidance beliefs about work accounted for 23% of the variance of disability in activities of daily living and 26% of the variance of work loss, even after allowing for severity of pain; fear-avoidance beliefs about physical activity explained an additional 9% of the variance of disability. These results confirm the importance of fear-avoidance beliefs and demonstrate that specific fear-avoidance beliefs about work are strongly related to work loss due to low back pain. These findings are incorporated into a biopsychosocial model of the cognitive, affective and behavioural influences in low back pain and disability. It is recommended that fear-avoidance beliefs should be considered in the medical management of low back pain and disability.

A validated, practical classification procedure for many persistent low back pain patients.

We have developed a simple procedure for assigning persistent low back pain patients to one of four mutually exclusive, hierarchically organized classes. The procedure relies on the spatial distribution of a patient's pain and the results of straight leg raise tests to make the assignment. We have applied the procedure to a large group of patients who sought treatment for persistent LBP at several university affiliated tertiary care clinics, and found that the resulting four classes of patients were significantly different from one another in their presentation, and in the way they were evaluated and treated by physicians. We concluded that the procedure may have practical research and clinical applications.

Pathogenesis of sciatic pain: role of herniated nucleus pulposus and deformation of spinal nerve root and dorsal root ganglion.

The basic pathophysiologic mechanisms related to disc herniation and sciatica are poorly understood. Recently it was demonstrated that nucleus pulposus from an intervertebral disc could induce structural and functional changes in adjacent nerve roots when applied epidurally, however, it is not known if such changes are painful. In a model for inducing disc herniation in the rat, we found that puncture of a lumbar disc with subsequent herniation of nucleus pulposus without nerve root compression, or chronic displacement of the 4th lumbar nerve root and ganglion, did not individually induce significant changes in thresholds for mechanical or thermal stimulation compared to sham-operated animals. However, the combination of disc puncture and displacement induced a reduction of the threshold for thermal stimulation, indicating hyperalgesia, that was present 2 days after surgery and gradually recovered during a 14-day period. These data and the associated description of this new model for experimental disc herniation may increase our understanding of the pathophysiologic events leading to sciatica and help in evaluating new modalities for diagnosis and treatment of disc herniation and sciatica.