Diminished neurokinin-1 receptor availability in patients with two forms of chronic visceral pain

Central sensitization and dysregulation of peripheral substance P and neurokinin-1 receptor (NK-1R) signaling are associated with chronic abdominal pain in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although positron emission tomography (PET) has demonstrated that patients with injury-related chronic pain have diminished NK-1R availability in the brain, it is unknown whether these deficits are present in IBD and IBS patients, who have etiologically distinct forms of non-injury-related chronic pain. This study’s aim was to determine if patients with IBD or IBS exhibit deficits in brain expression of NK-1Rs relative to healthy controls (HCs), the extent to which expression patterns differ across patient populations, and if these patterns differentially relate to clinical parameters. PET with [¹⁸F]SPA-RQ was used to measure NK-1R availability by quantifying binding potential (BP) in the 3 groups. Exploratory correlation analyses were performed to detect associations between NK-1R BP and physical symptoms. Compared to HCs, IBD patients had NK-1R BP deficits across a widespread network of cortical and subcortical regions. IBS patients had similar, but less pronounced deficits. BP in a subset of these regions was robustly related to discrete clinical parameters in each patient population. Widespread deficits in NK-1R BP occur in IBD and, to a lesser extent, IBS; however, discrete clinical parameters relate to NK-1R BP in each patient population. This suggests that potential pharmacological interventions that target NK-1R signaling may be most effective for treating distinct symptoms in IBD and IBS.     

Brain opioid receptor density predicts motor cortex stimulation efficacy for chronic pain

The clinical effects of motor cortex stimulation (MCS) for neuropathic pain (NP) is thought to be mediated primarily by the secretion of endogenous opioids in humans and in animal models. Because opioid receptor density is itself decreased in patients with NP, we investigated whether the magnitude and distribution of the remaining opioid receptors in patients with NP could be biological predictors of the pain-relieving effects of MCS. Using ¹¹C-diprenorphine positron emission tomography scans, opioid receptor availability was assessed in 15 patients suffering refractory NP, who subsequently received chronically implanted MCS. All patients underwent 2 preoperative baseline scans at 2-wk intervals and were clinically assessed after 7 mo of chronic MCS. The levels of preoperative opioid-binding in the insula, thalamus, periaqueductal gray, anterior cingulate, and orbitofrontal cortex were significantly and positively correlated with postoperative pain relief at 7 mo. Patients with receptor density values below the lower limits in age-matched controls in the thalamus, periaqueductal gray and contralateral insula were the least likely to benefit from MCS. Opioid-receptor availability as shown in preoperative positron emission tomography scans appears to be related to the efficacy of MCS in NP and may help clinicians to select the candidates most likely to benefit from this procedure.     

Predictive factors of chronic pain and disability in whiplash: A Delphi poll

The purpose of this study was to establish consensus on what factors might predict chronic pain and disability in whiplash injuries following motor vehicle collisions. A Delphi poll involving two rounds of data collection was used as a way to reach consensus among participating experts. Participating experts identified several physical, historical, psychological, and behavioral response factors that they believed were related to the development of chronic pain and related disability in people who have developed whiplash‐associated disorders. These included: (1) prior history: previous history of chronic pain; (2) physical factors: high severity of injury, presence of constant neck pain since the accident; (3) psychological factors: belief that pain mean danger and that he or she should avoid exercise, tendency to somatize, to have positive thoughts about pain, catastrophic thinking, low self‐efficacy expectancies, and to have symptoms of posttraumatic stress disorders; and (4) behavioral responses to symptoms: avoidance of activities that involve moving the neck through fear of experiencing more pain, and restriction in the use and movement of the neck. These findings may be used to help identify the specific domains that should be assessed in studies seeking to predict which individuals are at risk to develop chronic pain and disability following initial whiplash‐associated disorders sustained in crash. If these results are supported by future studies, then they could be used to help develop intervention programs that could prevent long‐term pain and disability in whiplash patients who are considered to be at risk to develop chronic disabling pain problems.     

The predictive value of attentional bias towards pain-related information in chronic pain patients: A diary study

Theoretical accounts of chronic pain hypothesize that attentional bias towards pain-related information is a maintaining or exacerbating factor, fuelling further pain, disability, and distress. However, empirical research testing this idea is currently lacking. In the present study, we investigated whether attentional bias towards pain-related information predicts daily pain-related outcomes in a sample of chronic pain patients (n = 69; M_age = 49.64 years; 46 females). During an initial laboratory session, attentional bias to pain-related information was assessed using a modified spatial cueing task. In advance, patients completed a number of self-report measures assessing current pain intensity, current disability, and pain duration. Subsequently, daily pain outcomes (self-reported pain severity, disability, avoidance behaviour, and distractibility) were measured for 2 weeks by means of an electronic diary. Results indicated that, although an attentional bias towards pain-related information was associated with the current level of disability and pain severity, it had no additional value above control variables in predicting daily pain severity, avoidance, distractibility, and disability. Attentional bias towards pain-related information did, however, moderate the relationship between daily pain severity and both daily disability and distractibility, indicating that, particularly in those patients with a strong attentional bias, increases in pain were associated with increased disability and distractibility. The use of interventions that diminish attentional bias may therefore be helpful to reduce daily disability and the level of distraction from current tasks despite the presence of pain in chronic pain patients.     

Comprehensive treatment for patients with chronic pain in a 12-step based substance use disorder program

Patients with chronic pain (CP) and substance use disorder (SUD) are complex, not yet adequately described, and in need of comprehensive treatments that address both diseases concurrently. Our objectives were to (a) describe a cohort of CP patients who failed traditional treatment (mainly opioids) – then developed opioid use disorder (OUD) and other SUDs and (b) evaluate a comprehensive inpatient treatment program for these patients. Patients were enrolled in an inpatient CP program. Treatment consisted of medical detoxification, group process/education, external and internal qigong, osteopathic manual medicine, and qigong-based mindfulness. Patients also received 20 h per week of 12-step recovery-based SUD treatment. Patients were evaluated at the beginning of treatment (first assessment, day 1–5 range) and at days 30 and 45. Assessments were: Beck Depression Inventory-II, Brief Pain Inventory, West Haven-Yale Multidimensional Pain Inventory (patient section), and McGill Pain Questionnaire. The Global Impression of Change Scale was administered at day 45. A mixed model analysis was used to evaluate treatment progress. Demographic data revealed an older cohort with OUD, other SUDs, and multiple pain diagnoses who failed traditional treatment. Questionnaire evaluations were consistent and similar across all of the above measures: patients’ scores showed marked, statistically significant improvements in depression, pain, and quality of life ratings. The most substantial improvements occurred between the first and second assessments. The findings are sufficiently encouraging to warrant further evaluation of the protocol and to plan comparative studies.     

Upregulation of presynaptic proteins and protein kinases associated with enhanced glutamate release from axonal terminals (synaptosomes) of the medial prefrontal cortex in rats with neuropathic pain

Although nerve injury-induced long-term postsynaptic changes have been investigated, less is known regarding the molecular mechanisms within presynaptic axonal terminals. We investigated the molecular changes in presynaptic nerve terminals underlying chronic pain-induced plastic changes in the medial prefrontal cortex (mPFC). After neuropathic pain was induced by spared nerve injury (SNI) in rats, we assessed the release of the excitatory neurotransmitter glutamate by using in vitro synaptosomal preparations from the mPFC. We also measured the levels of synaptic proteins and protein kinases in synaptosomes using Western blotting. The results showed that unilateral long-term SNI augmented depolarization-evoked glutamate release from synaptosomes of the bilateral mPFC. This result was confirmed by a rapid destaining rate of FM1-43 dye in SNI-operated rats. Unilateral long-term nerve injury also significantly increased synaptic proteins (including synaptophysin, synaptotagmin, synaptobrevin, syntaxin, and 25-kDa synaptosome-associated protein) in synaptosomal fractions from the bilateral mPFC, and ultrastructure images demonstrated increased synaptic vesicular profiles in synaptosomes from SNI animals. Chronic pain upregulated the phosphorylation of endogenous protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Ca²⁺/calmodulin-dependent kinase II (CaMKII), and synapsin I, the primary presynaptic target of ERK1/2 and CaMKII. Both presynaptic proteins and protein kinases were upregulated after SNI in a time-dependent manner. These results indicate that the long-term neuropathic pain-induced enhancement of glutamate release in the mPFC is linked to increased synaptic vesicle proteins and the activation of the ERK1/2- and CaMKII-synapsin signaling cascade in presynaptic axonal terminals.     

Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study

Chronic pelvic pain (CPP) is a highly prevalent pain condition, estimated to affect 15%-20% of women in the United States. Endometriosis is often associated with CPP, however, other factors, such as preexisting or concomitant changes of the central pain system, might contribute to the development of chronic pain. We applied voxel-based morphometry to determine whether women with CPP with and without endometriosis display changes in brain morphology in regions known to be involved in pain processing. Four subgroups of women participated: 17 with endometriosis and CPP, 15 with endometriosis without CPP, 6 with CPP without endometriosis, and 23 healthy controls. All patients with endometriosis and/or CPP were surgically confirmed. Relative to controls, women with endometriosis-associated CPP displayed decreased gray matter volume in brain regions involved in pain perception, including the left thalamus, left cingulate gyrus, right putamen, and right insula. Women with CPP without endometriosis also showed decreases in gray matter volume in the left thalamus. Such decreases were not observed in patients with endometriosis who had no CPP. We conclude that CPP is associated with changes in regional gray matter volume within the central pain system. Although endometriosis may be an important risk factor for the development of CPP, acting as a cyclic source of peripheral nociceptive input, our data support the notion that changes in the central pain system also play an important role in the development of chronic pain, regardless of the presence of endometriosis.     

The persistence of pain behaviors in patients with chronic back pain is independent of pain and psychological factors

The primary purpose of the present study was to examine the temporal stability of communicative and protective pain behaviors in patients with chronic back pain. The study also examined whether the stability of pain behaviors could be accounted for by patients’ levels of pain severity, catastrophizing, or fear of movement. Patients (n = 70) were filmed on two separate occasions (i.e., baseline, follow-up) while performing a standardized lifting task designed to elicit pain behaviors. Consistent with previous studies, the results provided evidence for the stability of pain behaviors in patients with chronic pain. The analyses indicated that communicative and protective pain behavior scores did not change significantly from baseline to follow-up. In addition, significant test-retest correlations were found between baseline and follow-up pain behavior scores. The results of hierarchical multiple regression analyses further showed that pain behaviors remained stable over time even when accounting for patients’ levels of pain severity. Regression analyses also showed that pain behaviors remained stable when accounting for patients’ levels of catastrophizing and fear of movement. Discussion addresses the potential contribution of central neural mechanisms and social environmental reinforcement contingencies to the stability of pain behaviors. The discussion also addresses how treatment interventions specifically aimed at targeting pain behaviors might help to augment the overall impact of pain and disability management programs.     

Quality of life in chronic pain is more associated with beliefs about pain, than with pain intensity.

OBJECTIVES: The objectives of this study were to investigate pain cognitions and quality of life of chronic pain patients referred to a multi-disciplinary university pain management clinic and to search for predictors of quality of life. METHODS: A heterogeneous group of 1208 chronic pain patients referred to the Maastricht university hospital pain clinic participated in this cross-sectional study. At the initial assessment, all patients completed a set of questionnaires on demographic variables, cause, location, pain intensity (McGill pain questionnaire, MPQ), pain coping and beliefs (pain coping and cognition list, PCCL), pain catastrophising (pain catastrophising scale, PCS) and eight dimensions of quality of life (Rand-36). RESULTS: The results showed that the present sample of heterogeneous pain patients reported low quality of life on each domain and significantly lower scores than has been found in previous studies with other Dutch chronic pain populations. Patients with low back pain and multiple pain localisations experienced most functional limitations. Women reported more pain, more catastrophising thoughts about pain, more disability and lower vitality and general health. When tested in a multiple regression analysis, pain catastrophising turned out to be the single most important predictor of quality of life. Especially social functioning, vitality, mental health and general health are significantly associated with pain catastrophising. CONCLUSIONS: Patients from a multi-disciplinary university pain clinic experience strikingly low quality of life, whereby low back pain patients and patients with multiple pain localisations have the lowest quality of life. Pain catastrophising showed the strongest association with quality of life, and stronger than pain intensity.     

Post-operative pain behavior in rats is reduced after single high-concentration capsaicin application

Surgical procedures associated with tissue injury are often followed by increased sensitivity to innocuous and noxious stimuli in the vicinity of the surgical wound. The aim of this study was to evaluate the role of transient receptor potential vanilloid 1 receptor (TRPV1) containing nociceptors in this process, by their functional inactivation using a high-concentration intradermal injection of capsaicin in a rat plantar incision model. Paw withdrawal responses to mechanical stimuli (von Frey filaments 10-367mN) and to radiant heat applied on plantar skin were tested in animals treated with capsaicin or the vehicle 6 days and 24h before or 2h after the incision was made. In the vehicle-treated animals, mechanical and thermal sensitivity increased significantly 1-96h following the incision. Capsaicin applied 24h before the surgery was most effective and significantly diminished the development of post-incisional mechanical allodynia and hyperalgesia. Thermal hypoalgesia was present in the incised paw after the capsaicin treatment. Capsaicin application 6 days before the incision induced thermal hypoalgesia before the incision but did not prevent completely the thermal hyperalgesia after the incision, while there was also a reduction of mechanical hypersensitivity. Application of the capsaicin injection after the incision showed its first effect at 2h after the injection and at 24h the effect was comparable with the 6 days pretreatment. Our results show an important role of TRPV1-containing nociceptors in the development of post-surgical hypersensitivity and suggest that local, high-concentration capsaicin treatment could be used to reduce it.     

Inhibition of c-Kit signaling is associated with reduced heat and cold pain sensitivity in humans

The tyrosine kinase receptor c-Kit is critically involved in the modulation of nociceptive sensitivity in mice. Ablation of the c-Kit gene results in hyposensitivity to thermal pain, whereas activation of c-Kit produces hypersensitivity to noxious heat, without altering sensitivity to innocuous mechanical stimuli. In this study, we investigated the role of c-Kit signaling in human pain perception. We hypothesized that subjects treated with Imatinib or Nilotinib, potent inhibitors of tyrosine kinases including c-Kit but also Abl1, PDFGFRα, and PDFGFRβ, that are used to treat chronic myeloid leukemia (CML), would experience changes in thermal pain sensitivity. We examined 31 asymptomatic CML patients (14 male and 17 female) receiving Imatinib/Nilotinib treatment and compared them to 39 age- and sex-matched healthy controls (12 male and 27 female). We used cutaneous heat and cold stimulation to test normal and noxious thermal sensitivity, and a grating orientation task to assess tactile acuity. Thermal pain thresholds were significantly increased in the Imatinib/Nilotinib-treated group, whereas innocuous thermal and tactile thresholds were unchanged compared to those in the control group. In conclusion, our findings suggest that the biological effects of c-Kit inhibition are comparable in mice and humans in that c-Kit activity is required to regulate thermal pain sensitivity but does not affect innocuous thermal and mechanical sensation. The effect on experimental heat pain observed in our study is comparable to those of several common analgesics; thus modulation of the c-Kit pathway can be used to specifically modulate noxious heat and cold sensitivity in humans.     

Mental defeat is linked to interference,distress and disability in chronic pain

Mental defeat is a psychological construct that has recently been applied to characterize the experience of chronic pain. Elevated levels of mental defeat have been identified in patients with chronic pain, and while its presence distinguishes treatment seeking from non-treatment seeking individuals, the link between mental defeat and disability in chronic pain is yet to be established. The current study investigated the extent to which mental defeat is associated with pain-related interference, distress and disability. A total of 133 participants completed the Pain Self Perception Scale that assessed mental defeat in relation to pain. Moreover, the participants were asked to complete a set of questionnaires that measured pain interference, distress, disability and other demographic (age, body mass index), clinical (pain intensity) and psychological (catastrophizing, worry, rumination and health anxiety) predictors of disability. Mental defeat was found to be strongly correlated with pain interference, sleep disturbance, anxiety, depression, functional disability and psychosocial disability. These correlations remained significant even when pain intensity and demographic variables were partialled out. Relative to chronic pain patients with lower levels of mental defeat, those with higher levels of mental defeat reported greater degree of pain interference, distress and disability. In a series of regression analyses, mental defeat emerged as the strongest predictor of pain interference, depression and psychosocial disability, whereas catastrophizing was the best predictor of sleep interference, anxiety and functional disability. These findings suggest that mental defeat may be an important mediator of distress and disability in chronic pain. Theoretical and clinical implications are discussed.     

H1受体介导对疼痛调节机制的影响

目的：利用胺H1受体遗传基因敲除模型鼠（－／－）与野生鼠（＋／＋）前脑切片进行灌流实验，探讨H1受体介导对疼痛调节机制影响的机理。方法：取（－／－）与（＋／＋）鼠的前脑组织纵横两方向切成450μm间隔的棒状脑切片，与林格氏液混合后装在双通体玻璃圆筒内，以微量泵抽出，通过装有脑切片的玻璃瓶中收集标本，对两次高钾浓度的林格氏液刺激的游离量S2／S1的比进行评价，并在填加各种药物下进行灌注实验，从而检测其对游离出的5－羟色胺（5－HT）的影响。结果：没加药物负荷的对照组中（－／－）和（＋／＋）之间的5－HT游离量没有差别。添加组胺抑制了5－HT的游离，（－／－）鼠没有被抑制，添加相关药物进行药理学的方法学的实验结果也支持组胺通过H1受体介导抑制5－HT的游离。结论：在中枢神经系统中，组胺通过H1受体的介导抑制5－HT的游离使疼痛感受性增强。     

An anti-nociceptive role for ceftriaxone in chronic neuropathic pain in rats

Glial glutamate transporter-1 (GLT-1) plays an essential role in the maintenance of glutamate homeostasis and is involved in the development and maintenance of pathological pain. The present study was undertaken (1) to observe the anti-nociceptive effects of ceftriaxone (Cef) in a chronic neuropathic pain model induced by chronic constrictive nerve injury (CCI) of the sciatic nerve and (2) to identify the role of spinal GLT-1 in the process. CCI induced significant thermal hyperalgesia and mechanical allodynia, which began from postoperative day 3 and lasted to day 21. This long-term hyperalgesia was accompanied by significant down-regulation of GLT-1 expression in the L4–L6 segments of the spinal dorsal horn, as revealed by immunohistochemistry and Western blot. Intraperitoneal preventive and therapeutic administration of Cef effectively prevented or reversed, respectively, the development of thermal hyperalgesia, mechanical allodynia, and GLT-1 down-regulation in the spinal dorsal horn. To further determine whether the above anti-nociceptive effects of Cef are a result of the up-regulation of spinal GLT-1 expression and its function, we further observed the effects of intrathecal administration of Cef in the same model. It was found that intrathecal administration of Cef led to the specific up-regulation of GLT-1 expression and glutamate uptake (³H-glutamate) in the spinal dorsal horn, and similar anti-nociceptive effects to those of intraperitoneal administration of Cef. The above effects of intrathecal Cef administration were all significantly inhibited by intrathecal administration of GLT-1 antisense oligodeoxynucleotides (As-ODNs). These results indicate that Cef plays an anti-nociceptive role by up-regulating spinal GLT-1 expression and its function.     

Systematic review of prevalence, correlates, and treatment outcomes for chronic non-cancer pain in patients with comorbid substance use disorder

Recent data suggest that comorbid substance use disorders (SUDs) are common among chronic non-cancer pain (CNCP) patients; however, prevalence rates vary across studies and findings are limited regarding treatment options for CNCP patients with comorbid SUD. The purpose of this systematic review is to assess the prevalence, associated demographic and clinical characteristics, and treatment outcomes for CNCP patients with comorbid SUD. We conducted searches from Ovid MEDLINE, PsychINFO, and PubMED from 1950 through February 2010 and retrieved the references. Thirty-eight studies met inclusion criteria and provided data that addressed our key questions. Three to forty-eight percent of CNCP patients have a current SUD. There are no demographic or clinical factors that consistently differentiate CNCP patients with comorbid SUD from patients without SUD, though SUD patients appear to be at greater risk for aberrant medication-related behaviors. CNCP patients with SUD are more likely to be prescribed opioid medications and at higher doses than CNCP patients without a history of SUD. CNCP patients with comorbid SUD do not significantly differ in their responses to treatment compared to CNCP patients without SUD, though the quality of this evidence is low. Limited data are available to identify predictors of treatment outcome. Although clinical experience and research suggests that SUDs are common among CNCP patients, only limited data are available to guide clinicians who treat this population. Research is needed to increase understanding of the prevalence, correlates, and responses to treatment of CNCP patients with comorbid SUDs.     

Brain networks predicting placebo analgesia in a clinical trial for chronic back pain

A fundamental question for placebo research is whether such responses are a predisposition, quantifiable by brain characteristics. We examine this issue in chronic back pain (CBP) patients who participated in a double-blind brain imaging (functional magnetic resonance imaging) clinical trial. We recently reported that when the 30 CBP participants were treated, for 2 weeks, with topical analgesic or no drug patches, pain and brain activity decreased independently of treatment type and thus were attributed to placebo responses. Here we examine in the same group brain markers for predicting placebo responses—that is, for differentiating between posttreatment persistent CBP (CBPp) and decreasing CBP (CBPd) groups. At baseline, pain and brain activity for rating spontaneous fluctuations of back pain were not different between the 2 groups. However, on the basis of brain activity differences after treatment, we identified that at baseline the extent of information shared (functional connectivity) between left medial prefrontal cortex and bilateral insula accurately (0.8) predicted posttreatment groups. This was validated in an independent cohort. Additionally, by means of frequency domain contrasts, we observe that at baseline, left dorsolateral prefrontal cortex high-frequency oscillations also predicted treatment outcomes and identified an additional set of functional connections distinguishing treatment outcomes. Combining medial and lateral prefrontal functional connections, we observe a statistically higher accuracy (0.9) for predicting posttreatment groups. These findings indicate that placebo response can be identified a priori at least in CBP, and that neuronal population interactions between prefrontal cognitive and pain processing regions predetermine the probability of placebo response in the clinical setting.     

Neuregulin 1 is a pronociceptive cytokine that is regulated by progesterone in the spinal cord: Implications for sex specific pain modulation

Sex differences in the magnitude of response to thermal and tactile stimuli have been demonstrated in both clinical and animal studies. Females typically display lower threshold responses to painful stimuli as compared to males. We have previously observed sexually dimorphic expression of the growth factor, neuregulin 1 (NRG1) following L5 nerve root ligation (LR) in male and female rats. In the present study, we sought to determine which gonadal hormones were involved in regulating NRG1 expression following L5 nerve root ligation. We observed that expression of NRG1 mRNA and the neuregulin receptors, ErbB2 and ErbB4 in the lumbar spinal cord was facilitated by the presence of progesterone in female rats following L5 nerve root ligation. An increase in NRG1 protein and NRG1 immunoreactivity was also observed in the ipsilateral spinal cord of progesterone treated female rats as compared to ovariectomized female rats and male rats at day 14 following LR. NRG1 immunoreactivity was equally colocalized with either the astrocytic marker, GFAP, and with NeuN labeled neurons 14days following L5 nerve root ligation. Intrathecal administration of recombinant NRG1‐β1 protein significantly decreased the hindpaw tactile withdrawal threshold in male rats, ovariectomized female rats, and progesterone treated female rats. These results demonstrate a role for progesterone‐dependent regulation of glial and/or neuronal neuregulin 1 in female rats in mediating sex differences in nociception. Furthermore, our results suggest that NRG1 may be involved in central sensitization during the maintenance phase, but not in the initiation of persistent pain in female rats.