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Complex Regional Pain Syndrome (CRPS) develops after fracture. The acute CRPS phenotype resembles exaggerated inflammation which is explained by local and systemic activation of a pro-inflammatory network including peptides and cytokines. Epidemiologic data suggest that inactivation of the peptidase angiotensin converting enzyme (ACE) in patients treated for hypertension increases the odds to develop CRPS. This hint lead us to investigate the serum protease network activity in CRPS patients vs. respective controls. For this purpose, we developed a dabsyl-bradykinin (DBK)-based assay and used it to investigate CRPS patients, as well as healthy (HC) and pain (painful diabetic neuropathy; dPNP) controls. The major result is that the degradation of DBK to fragments 1-8 and 1-5 in HC and dPNP is shifted to higher values for DBK1-8 and lower values for DBK 1-5 at one hour of incubation in CRPS patients. Using this novel reporter peptide assay, we have been able to show that the resolving protease network for mediators like BK might be different in CRPS patients; having a look at the the clinical signs, which resemble inflammation, this resolving protease network is probably less effective in CRPS.
Learn More >Sleep loss increases the experience of pain. However, the brain mechanisms underlying altered pain processing following sleep deprivation are unknown. Moreover, it remains unclear whether ecologically modest night-to-night changes in sleep, within an individual, confer consequential day-to-day changes in experienced pain. Here, we demonstrate that acute sleep-deprivation amplifies pain reactivity within human (male and female) primary somatosensory cortex yet blunts pain-reactivity in higher-order valuation and decision-making regions of the striatum and insula cortex. Consistent with this altered neural signature, we further show that sleep deprivation expands the temperature range for classifying a stimulus as painful, specifically through a lowering of pain thresholds. Moreover, the degree of amplified reactivity within somatosensory cortex following sleep deprivation significantly predicts this expansion of experienced pain across individuals. Finally, outside of the laboratory setting, we similarly show that even modest nightly changes in sleep quality (increases and decreases) an individual determine consequential day-to-day changes in experienced pain (decreases and increases, respectively). Together, these data provide a central brain framework underlying the impact of sleep loss on pain, and furthermore, establish that the association between sleep and pain is expressed in a night-to-day, bidirectional relationship within a sample of the general population. More broadly, our findings highlight sleep as a novel therapeutic target for pain management within and outside the clinic, including circumstances where sleep is frequently short yet pain is abundant (e.g. the hospital setting).Are you experiencing pain? Did you have a bad night of sleep? This study provides underlying brain and behavioral mechanisms explaining this common co-occurrence. We show that sleep deprivation enhances pain responsivity within the primary sensing regions of the brain's cortex yet blunts activity in other regions that modulate pain processing-the striatum and insula. We further establish that even subtle night-to-night changes in sleep in a sample of the general population predict consequential day-to-day changes in pain (bidirectionally). Considering the societal rise in chronic pain conditions in lock-step with the decline in sleep time through the industrial world, our data support the hypothesis that these two trends may not simply be co-occurring but are significantly inter-related.
Learn More >Mast cells can be found in close proximity to peripheral nerve endings where, upon activation, they release a broad range of pro-inflammatory cytokines and chemokines. However, the precise mechanism underlying this so-called neurogenic inflammation and associated pain has remained elusive. Here we report that the mast-cell-specific receptor Mrgprb2 mediates inflammatory mechanical and thermal hyperalgesia and is required for recruitment of innate immune cells at the injury site. We also found that the neuropeptide substance P (SP), an endogenous agonist of Mrgprb2, facilitates immune cells' migration via Mrgprb2. Furthermore, SP activation of the human mast cell led to the release of multiple pro-inflammatory cytokines and chemokines via the human homolog MRGPRX2. Surprisingly, the SP-mediated inflammatory responses were independent of its canonical receptor, neurokinin-1 receptor (NK-1R). These results identify Mrgprb2/X2 as an important neuroimmune modulator and a potential target for treating inflammatory pain.
Learn More >Chronic pain is associated with neuroplastic changes in the amygdala that may promote hyper-responsiveness to mechanical and thermal stimuli (allodynia and hyperalgesia) and/or enhance emotional and affective consequences of pain. Stress promotes dynorphin-mediated signaling at the kappa opioid receptor (KOR) in the amygdala and mechanical hypersensitivity in rodent models of functional pain. Here, we tested the hypothesis that KOR circuits in the central nucleus of the amygdala (CeA) undergo neuroplasticity in chronic neuropathic pain resulting in increased sensory and affective pain responses. After spinal nerve ligation (SNL) injury in rats, pretreatment with a long-acting KOR antagonist, nor-binaltorphimine (nor-BNI), subcutaneously or through microinjection into the right CeA, prevented conditioned place preference (CPP) to intravenous gabapentin, suggesting that nor-BNI eliminated the aversiveness of ongoing pain. By contrast, systemic or intra-CeA administration of nor-BNI had no effect on tactile allodynia in SNL animals. Using whole-cell patch-clamp electrophysiology, we found that nor-BNI decreased synaptically evoked spiking of CeA neurons in brain slices from SNL but not sham rats. This effect was mediated through increased inhibitory postsynaptic currents, suggesting tonic disinhibition of CeA output neurons due to increased KOR activity as a possible mechanism promoting ongoing aversive aspects of neuropathic pain. Interestingly, this mechanism is not involved in SNL-induced mechanical allodynia. Kappa opioid receptor antagonists may therefore represent novel therapies for neuropathic pain by targeting aversive aspects of ongoing pain while preserving protective functions of acute pain.
Learn More >Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and toxin modulation remains ill-defined. Protoxin-II (ProTx2) from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1.7 channel. Here, we visualize ProTx2 in complex with voltage-sensor domain II (VSD2) from Nav1.7 using X-ray crystallography and cryoelectron microscopy. Membrane partitioning orients ProTx2 for unfettered access to VSD2, where ProTx2 interrogates distinct features of the Nav1.7 receptor site. ProTx2 positions two basic residues into the extracellular vestibule to antagonize S4 gating-charge movement through an electrostatic mechanism. ProTx2 has trapped activated and deactivated states of VSD2, revealing a remarkable ∼10 Å translation of the S4 helix, providing a structural framework for activation gating in voltage-gated ion channels. Finally, our results deliver key templates to design selective Nav channel antagonists.
Learn More >Prescription opioids are involved in 40% of all deaths from opioid overdose in the United States and are commonly the first opioids encountered by individuals with opioid use disorder. It is unclear whether the pharmaceutical industry marketing of opioids to physicians is associated with mortality from overdoses.
Learn More >Acute pain is adaptive, but chronic pain is a global challenge. Many chronic pain syndromes are peripheral in origin and reflect hyperactivity of peripheral pain-signaling neurons. Current treatments are ineffective or only partially effective and in some cases can be addictive, underscoring the need for better therapies. Molecular genetic studies have now linked multiple human pain disorders to voltage-gated sodium channels, including disorders characterized by insensitivity or reduced sensitivity to pain and others characterized by exaggerated pain in response to normally innocuous stimuli. Here, we review recent developments that have enhanced our understanding of pathophysiological mechanisms in human pain and advances in targeting sodium channels in peripheral neurons for the treatment of pain using novel and existing sodium channel blockers. Expected final online publication date for the Annual Review of Neuroscience Volume 42 is July 8, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Learn More >Based on few clinical trials, flunarizine is considered a first-line prophylactic treatment for migraine in several guidelines. In this meta-analysis, we examined the pooled evidence for its effectiveness, tolerability, and safety. Prospective randomized controlled trials of flunarizine as a prophylaxis against migraine were identified from a systematic literature search, and risk of bias was assessed for all included studies. Reduction in mean attack frequency was estimated by calculating the mean difference (MD), and a series of secondary outcomes-including adverse events (AEs)-were also analyzed. The database search yielded 879 unique records. Twenty-five studies were included in data synthesis. We scored 31/175 risk of bias items as "high," with attrition as the most frequent bias. A pooled analysis estimated that flunarizine reduces the headache frequency by 0.4 attacks per 4 weeks compared with placebo (5 trials, 249 participants: MD -0.44; 95% confidence interval -0.61 to -0.26). Analysis also revealed that the effectiveness of flunarizine prophylaxis is comparable with that of propranolol (7 trials, 1151 participants, MD -0.08; 95% confidence interval -0.34 to 0.18). Flunarizine also seems to be effective in children. The most frequent AEs were sedation and weight increase. Meta-analyses were robust and homogenous, although several of the included trials potentially suffered from high risk of bias. Unfortunately, reporting of AEs was inconsistent and limited. In conclusion, pooled analysis of data from partially outdated trials shows that 10-mg flunarizine per day is effective and well tolerated in treating episodic migraine-supporting current guideline recommendations.
Learn More >Electroacupuncture (EA) is widely used in clinical settings to reduce inflammatory pain. Islet-cell autoantigen 69 (ICA69) has been reported to regulate long-lasting hyperalgesia in mice. ICA69 knockout led to reduced protein interacting with C-kinase 1 (PICK1) expression and increased glutamate receptor subunit 2 (GluR2) phosphorylation at Ser880 in spinal dorsal horn. In this study, we evaluated the role of ICA69 in the antihyperalgesic effects of EA and the underlying mechanism through regulation of GluR2 and PICK1 in spinal dorsal horn. Hyperalgesia was induced in mice with subcutaneous plantar injection of complete Freund adjuvant (CFA) to cause inflammatory pain. Electroacupuncture was then applied for 30 minutes every other day after CFA injection. When compared with CFA group, paw withdrawal frequency of CFA+EA group was significantly decreased. Remarkable increases in Ica1 mRNA expression and ICA69 protein levels on the ipsilateral side were detected in the CFA+EA group. ICA69 expression reached the peak value around day 3. More importantly, ICA69 deletion impaired the antihyperalgesic effects of EA on GluR2-p, but PICK1 deletion could not. Injecting ICA69 peptide into the intrathecal space of ICA69-knockout mice mimicked the effects of EA analgesic and inhibited GluR2-p. Electroacupuncture had no effects on the total protein of PICK1 and GluR2. And, EA could increase the formation of ICA69-PICK1 complexes and decrease the amount of PICK1-GluR2 complexes. Our findings indicate that ICA69 mediates the antihyperalgesic effects of EA on CFA-induced inflammatory pain by regulating spinal GluR2 through PICK1 in mice.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Learn More >Normative data for chronic pain questionnaires are essential to the interpretation of aggregate scores on these questionnaires, for both clinical trials and clinical practice. In this study we summarised data from 13,343 heterogeneous patients on several commonly used pain questionnaires that were routinely collected from 36 pain clinics in Australia and New Zealand as part of the electronic Persistent Pain Outcomes Collaboration (ePPOC) including the Brief Pain Inventory (BPI); the Depression Anxiety and Stress Scales (DASS); the Pain Self-Efficacy Questionnaire (PSEQ); and the Pain Catastrophizing Scale (PCS). The data are presented as summarised normative data, broken down by demographic (age, sex, work status, etc) and pain site/medical variables. The mean BPI severity score was 6.4 (moderate-severe) and mean interference score was 7.0. The mean DASS depression score was 20.2 (moderate-severe), mean DASS anxiety was 14.0 (moderate), and mean DASS stress was 21.0 (moderate). The mean PCS scores were 10.0, 5.9, 14.1 and 29.8 for rumination, magnification, helplessness and total, respectively. The mean PSEQ score was 20.7. Males had slightly worse scores than females on some scales. Scores tended to worsen with age until 31-50 years, after which they improved. Scores were worse for those who had a greater number of pain sites, were unemployed, were injury compensation cases, or whose triggering event was a motor vehicle accident or injury at work or home. These results and comparisons with data on the same measures from other countries, as well as their uses in both clinical practice and clinical trials, are discussed.
Learn More >With the approval of calcitonin gene-related peptide (CGRP) and CGRP receptor monoclonal antibodies by the Federal Drug Administration, a new era in the treatment of migraine patients is beginning. However, there are still many unknowns in terms of CGRP mechanisms of action that need to be elucidated to allow new advances in migraine therapies. CGRP has been studied both clinically and preclinically since its discovery. Here we review some of the preclinical data regarding CGRP in animal models of migraine.
Learn More >The counterirritation phenomenon known as conditioned pain modulation, or diffuse noxious inhibitory control in animals, is of increasing interest due to its utility in predicting chronic pain and treatment response. It features considerable interindividual variability, with large subsets of pain patients and even normal volunteers exhibiting hyperalgesia rather than hypoalgesia during or immediately after receiving a conditioning stimulus. We observed that mice undergoing tonic inflammatory pain in the abdominal cavity (the conditioning stimulus) display hyperalgesia, not hypoalgesia, to noxious thermal stimulation (the test stimulus) applied to the hindpaw. In a series of parametric studies, we show that this hyperalgesia can be reliably observed using multiple conditioning stimuli (acetic acid and orofacial formalin), test stimuli (hindpaw and forepaw-withdrawal, tail-withdrawal, hot-plate, and von Frey tests) and genotypes (CD-1, DBA/2, and C57BL/6 mice and Sprague-Dawley rats). Although the magnitude of the hyperalgesia is dependent on the intensity of the conditioning stimulus, we find that the direction of effect is dependent on the effective test stimulus intensity, with lower-intensity stimuli leading to hyperalgesia and higher-intensity stimuli leading to hypoalgesia.
Learn More >Stability of local medial prefrontal cortex (mPFC) network activity is believed to be critical for sustaining cognitive processes such as working memory (WM) and decision making. Dysfunction of the mPFC has been identified as a leading cause to WM deficits in several chronic pain conditions; however, the underlying mechanisms remain largely undetermined. Here, to address this issue, we implanted multichannel arrays of electrodes in the prelimbic region of the mPFC and recorded the neuronal activity during a food-reinforced delayed nonmatch to sample (DNMS) task of spatial WM. In addition, we used an optogenetic technique to selectively suppress the activity of excitatory pyramidal neurons that are considered the neuronal substrate for memory retention during the delay period of the behavioral task. Within-subject behavioral performance and pattern of neuronal activity were assessed after the onset of persistent pain using the spared nerve injury model of peripheral neuropathy. Our results show that the nerve lesion caused a disruption in WM and prelimbic spike activity and that this disruption was reversed by the selective inhibition of prelimbic glutamatergic pyramidal neurons during the delay period of the WM task. In spared nerve injury animals, photoinhibition of excitatory neurons improved the performance level and restored neural activity to a similar profile observed in the control animals. In addition, we found that selective inhibition of excitatory neurons does not produce antinociceptive effects. Together, our findings suggest that disruption of balance in local prelimbic networks may be crucial for the neurological and cognitive deficits observed during painful syndromes.
Learn More >Our recent work has shown that the early-life administration of vincristine (VNC), commonly used to treat pediatric cancers, evokes mechanical pain hypersensitivity in rats that emerges during adolescence and persists into adulthood. However, the underlying mechanisms remain unclear, as nothing is known about how neonatal VNC treatment influences peripheral and central nociceptive processing at the cellular level. Here, we used in vitro intracellular microelectrode and whole-cell patch-clamp recordings to evaluate the consequences of early-life VNC administration on the intrinsic membrane properties of adolescent dorsal root ganglion and spinal superficial dorsal horn neurons. The results demonstrate that VNC treatment increased the prevalence and rate of repetitive firing in both large- and medium-diameter sensory neurons, while reducing repetitive firing in small-diameter neurons, in comparison with vehicle-treated littermate controls. By contrast, passive membrane properties and peripheral conduction velocities were similar between experimental groups across all classes of primary afferents. Within the adolescent superficial dorsal horn, neonatal VNC exposure significantly enhanced the intrinsic membrane excitability of lamina I spinoparabrachial neurons, as evidenced by a decrease in rheobase and elevation of repetitive firing frequency compared with controls. Meanwhile, putative interneurons within lamina I exhibited a reduction in repetitive action potential discharge after early-life chemotherapy. Collectively, these findings suggest that neonatal VNC treatment evokes cell type-specific changes in intrinsic excitability at multiple levels of the ascending pain pathway. Overall, this work lays an essential foundation for the future exploration of the ionic mechanisms that drive chemotherapy-induced chronic pain in children and adolescents.
Learn More >The peripherally expressed voltage-gated sodium Na1.7 (gene SCN9A) channel boosts small stimuli to initiate firing of pain-signaling dorsal root ganglia (DRG) neurons and facilitates neurotransmitter release at the first synapse within the spinal cord. Mutations in SCN9A produce distinct human pain syndromes. Widely acknowledged as a "gatekeeper" of pain, Na1.7 has been the focus of intense investigation but, to date, no Na1.7-selective drugs have reached the clinic. Elegant crystallographic studies have demonstrated the potential of designing highly potent and selective Na1.7 compounds but their therapeutic value remains untested. Transcriptional silencing of Na1.7 by a naturally expressed antisense transcript has been reported in rodents and humans but whether this represents a viable opportunity for designing Na1.7 therapeutics is currently unknown. The demonstration that loss of Na1.7 function is associated with upregulation of endogenous opioids and potentiation of mu- and delta-opioid receptor activities, suggests that targeting only Na1.7 may be insufficient for analgesia. However, the link between opioid-dependent analgesic mechanisms and function of sodium channels and intracellular sodium-dependent signaling remains controversial and disputed. Thus, additional new targets – regulators, modulators – are needed. In this context, we mine the literature for the known interactome of Na1.7 with a focus on protein interactors that affect the channel's trafficking or link it to opioid signaling. As a case study, we present antinociceptive evidence of allosteric regulation of Na1.7 by the cytosolic collapsin response mediator protein 2 (CRMP2). Throughout discussions of these possible new targets, we offer thoughts on the therapeutic implications of modulating Na1.7 function in chronic pain.
Learn More >The primary sensory cortex processes competitive sensory inputs. Ablation of these competitive inputs induces neuroplastic changes in local cortical circuits. However, information concerning cortical plasticity induced by a disturbance of competitive nociceptive inputs is limited. Nociceptive information from the maxillary and mandibular molar pulps converges at the border between the ventral secondary somatosensory cortex (S2) and insular oral region (IOR); therefore, S2/IOR is a suitable target for examining the cortical changes induced by a disturbance of noxious inputs, which often causes neuropathic pain and allodynia. We focused on the plastic changes in S2/IOR excitation in a model of rats subjected to inferior alveolar nerve transection (IANX). Our optical imaging using a voltage-sensitive dye (VSD) revealed that the maxillary molar pulp stimulation-induced excitatory propagation was expanded one to two weeks after IANX at the macroscopic level. At the cellular level, based on Ca imaging using two-photon microscopy, the amplitude of the Ca responses and the number of responding neurons in S2/IOR increased in both excitatory and inhibitory neurons. The laser scanning photostimulation (LSPS) revealed that Layer II/III pyramidal and GABAergic fast-spiking neurons in S2/IOR received larger excitatory inputs from Layer IV in the IANX models, which supports the findings obtained by the macroscopic and microscopic optical imaging. Furthermore, the inhibitory postsynaptic inputs to the pyramidal neurons were decreased in the IANX models, suggesting suppression of inhibitory synaptic transmission onto excitatory neurons. These results suggest that IANX induces plastic changes in S2/IOR by changing the local excitatory and inhibitory circuits.
Learn More >The calcitonin gene-related peptide (CGRP) receptor is composed of the calcitonin receptor-like receptor (CLR, a class B GPCR) and a single-pass membrane protein known as receptor activity modifying protein type 1 (RAMP1). The levels of the CGRP peptide increase during a migraine attack and infusion of CGRP can provoke a migraine attack. Consequently, there is much interest in inhibiting the actions of CGRP as a way to control migraine. Here we describe the development of small molecule antagonists designed to bind to the CGRP receptor to block its action by preventing binding of the CGRP peptide. We also describe the development of antibody drugs, designed to bind either to the CGRP receptor to block its action, or to bind directly to the CGRP peptide. The field has been very active, with one antibody drug approved and three antibody drugs in phase III clinical trial. Initial programs on the development CGRP antagonists were frustrated by liver toxicity but the current outlook is very promising with five small molecule antagonists in various stages of clinical trial.
Learn More >The opioid risk tool (ORT) is a commonly employed measure of risk of aberrant drug related behaviors (ADRB) in patients with chronic pain prescribed opioid therapy. In this study the discriminant predictive validity of the ORT was evaluated in a unique cohort of patients with chronic nonmalignant pain (CNMP) on long-term opioid therapy (LTOT) that displayed no evidence of developing an opioid use disorder (OUD) and a sample of patients with CNMP that developed an OUD after commencing opioid therapy. Results revealed that the original ORT was able to discriminate between patients with and without OUDs (OR=1.624; CI 95%: 1.539-1.715, p< 0.001). A weighted ORT eliminating the gender specific history of preadolescent sexual abuse item revealed comparable results (OR= 1.648; CI 95%: 1.539-1.742, p< 0.001). A revised unweighted ORT (ORT-OUD) removing the history of preadolescent sexual abuse item was notably superior in predicting the development of OUD in patients with CNMP on LTOT (OR= 3.085; CI 95%: 2.725-3.493, p< 0.001) with high specificity (0.851; CI 95%: 0.811-0.885), sensitivity (0.854; 95% CI: 0,799-0.898), positive (0.757; CI 95%: 0.709-0.799) and negative (0.914; CI 95%: 0.885-0.937) predictive values. Perspective: The revised ORT (ORT-OUD) is the first tool developed on a unique cohort to predict the risk of developing an OUD in patients with CNMP receiving opioid therapy, as opposed to ADRB that can reflect a number of other issues. The ORT-OUD has clinical utility in providing clinicians a simple, validated method to rapidly screen for the risk of developing OUD in patients on or being considered for opioid therapy.
Learn More >Learning processes have been discussed in the context of pain chronicity for decades. Particularly, operant conditioning has been used to experimentally induce and modulate pain in healthy humans. In this systematic review and meta-analysis, research findings on pain facilitation (hyperalgesic effect) and pain elicitation (allodynic effect) are evaluated. The review was performed according to the PRISMA guideline and an a priori published protocol. Nine databases were searched for relevant publications: PubMed, Cochrane Register of Controlled Trials (CENTRAL), Web of Science™, ScienceDirect, EBSCO, PsycINFO, MEDLINE, PsycARTICLES and CINAHL. Studies were included if they investigated pain-free humans, exposed to an operant conditioning procedure of pain. Two independent assessors screened publications against eligibility criteria and assessed the risk of bias (RoB) with the Cochrane RoB scale. A total of 3155 records were screened of which 8 were included into the qualitative (401 participants) and 5 into the quantitative (110 participants) synthesis. Results showed that hyperalgesic (standardized mean difference [SMD] of -0.80, 95% CI: -1.33 to -0.27, p = 0.003) and allodynic effects (-1.27, 95% CI: -2.46 to -0.08, p = 0.04) can be induced in healthy humans, indicating that pain can be shaped by contingencies of reinforcement. However, the uncertainty of the effect is relatively high, mostly due to the small number of included studies, demand characteristics and the risk of bias. This is especially relevant for studies on allodynic effects where the decrease in nociception should be more rigorously controlled. PERSPECTIVE: Operant conditioning can be a mechanism of pain chronicity. All experimental studies investigating this hypothesis have been identified and summarized. It has been demonstrated that allodynic and hyperalgesic effects can be induced by operant conditioning.
Learn More >Low-voltage activated T-type calcium channels mediate essential functions in the nervous system, and alteration of channel activity is causally linked to a number of neurological conditions. Therefore, T-type channels hold great promise as pharmacological targets for new medicines. In this Viewpoint, we discuss the potential of T-type channels as druggable targets and reevaluate the strategies available for developing therapeutically efficient and specific modulators of this channel.
Learn More >Low back pain is a common cause of chronic pain and disability. It is modeled in rodents by chronically compressing the lumbar dorsal root ganglia (DRG) with small metal rods, resulting in ipsilateral mechanical and cold hypersensitivity, and hyperexcitability of sensory neurons. Sodium channels are implicated in this hyperexcitability, but the responsible isoforms are unknown. In this study, we used siRNA- mediated knockdown of the pore-forming Na1.6 and regulatory Naβ4 sodium channel isoforms that have been previously implicated in a different model of low back pain caused by locally inflaming the L5 DRG. Knockdown of either subunit markedly reduced spontaneous pain and mechanical and cold hypersensitivity induced by DRG compression, and reduced spontaneous activity and hyperexcitability of sensory neurons with action potentials <1.5 msec (predominately cells with myelinated axons, based on conduction velocities measured in a subset of cells) 4 days after DRG compression. These results were similar to those previously obtained in the DRG inflammation model and some neuropathic pain models, in which sensory neurons other than nociceptors seem to play key roles. The cytokine profiles induced by DRG compression and DRG inflammation were also very similar, with upregulation of several type 1 pro-inflammatory cytokines and downregulation of type 2 anti-inflammatory cytokines. Surprisingly, the cytokine profile was largely unaffected by Naβ4 knockdown in either model. The Na1.6 channel, and the Naβ4 subunit that can regulate Na1.6 to enhance repetitive firing, play key roles in both models of low back pain; targeting the abnormal spontaneous activity they generate may have therapeutic value.
Learn More >The incidence of diabetes mellitus is approaching global epidemic proportions and should be considered a major health-care problem of modern societies in the twenty-first century. Diabetic neuropathy is a common chronic complication of diabetes and, although an adequate glycemic control can reduce the frequency of diabetic neuropathy in type 1 diabetes, the majority of type 2 diabetic patients will develop this complication. The underlying cellular and molecular mechanisms are still poorly understood, preventing the development of effective treatment strategies. However, accumulating evidence suggests that breakdown of the blood-nerve barrier (BNB) plays a pivotal pathophysiological role in diabetic neuropathy. In the present review, we highlight the structural and functional significance of the BNB in health and disease, focusing on the pathological molecular events leading to BNB dysfunction in diabetic neuropathy. In addition, we discuss potential molecular targets involved in BNB homeostasis that may pave the way toward novel therapeutic strategies for treating diabetic neuropathy.
Learn More >Background and aims Chronic pain is a leading cause to years lived with disability worldwide. However, few of the interventions used in pain medicine have proven efficacy, and evidence from the existing studies may not be valid for the general pain population. Therefore, it is of utmost need that we describe chronic pain conditions in their most relevant aspects, their various guises, as well as the real world outcomes of our clinical interventions. The most obvious and crude way to make these assessments are through large registries where patient characteristics, treatment characteristics (including but not limited to what, when, how often and by whom), treatment outcomes and patient outcomes are scrutinized and recorded. Methods and results This article describes in detail the design and baseline data of the comprehensive Oslo University Hospital Pain Registry (OPR). OPR is the local registry of the largest university and interdisciplinary outpatient pain clinic in Norway. Data registration started in October 2015, and approximately 1,000 patients are assessed and treated at the clinic each year. During the first 2 years of running the OPR (through September 2017), a total of 1,712 patient baseline reports were recorded from 2,001 patients. Clinicians enter data about relevant treatments and interventions, while patients provide self-reported data on aspects related to pain and pain management. The patients complete an electronic registration immediately before their first consultation at the outpatient pain clinic. The baseline questions of the OPR cover: Basic demographics; The Modified Oswestry Disability Index to assess general function; A pain drawing to assess pain location; Questions regarding the temporal aspects of pain; Six 0-10 Numeric Rating Scales to assess pain intensity and bothersomeness; The EQ-5D-5L to measure health-related quality of life; The Hopkins Symptom Check List-25 to assess psychological distress; A single question about self-rated health; The general self-efficacy scale to assess the patient's perceived self-efficacy; The Bodily Distress Syndrome checklist to assess functional disorders; The Injustice Experience Questionnaire to assess whether the patients experience injustice; Chalder Fatigue Questionnaire to assess fatigue; The Insomnia Severity Index to assesses the levels of insomnia symptoms; The Pain Catastrophizing Scale to measure pain catastrophizing and exaggerated negative orientation toward pain stimuli and pain experience; And the SF36v2 to assess patients' self-report of generic health and wellbeing. The baseline data show that chronic pain patients have a high degree of negative impact in all aspects of their lives. Conclusions and implications The OPR is the most comprehensive pain registry for multidisciplinary and interdisciplinary outpatient pain clinics in Norway. Detailed design of the registry and key baseline data are presented. Registries are of great value in that they enable real world effectiveness outcomes for patients with chronic pain conditions. The OPR can thus serve as a model for similar initiatives elsewhere. The OPR cohort may also serve as a historical control in future studies, both with experimental and observational design.
Learn More >A national crisis of opioid-related morbidity, mortality, and misuse has led to initiatives to address the appropriate role of opioids to treat pain. Deployment of a guideline from the Centers for Disease Control and Prevention to reduce the risks of opioid therapy has raised substantial clinical and public policy challenges. The agency anticipated implementation challenges and committed to reevaluating the guideline for intended and unintended effects on clinician and patient outcomes.
Learn More >Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a plethora of chemical and physical stimuli. These channels modulate ion entry, mediating a variety of neural signaling processes implicated in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be "ionotropic cannabinoid receptors." Although CB1 and CB2 are considered to be the canonical cannabinoid receptors, there is significant overlap between cannabinoids and ligands of TRP receptors. The first endogenous agonist of TRPV1 to be discovered was the endocannabinoid, anandamide (AEA). Similarly, arachidonyl dopamine (NADA) and AEA were the first endogenous TRPM8 antagonists discovered. Additionally, Δ-tetrahydrocannabinol (Δ-THC), the most abundant psychotropic compound in cannabis, acts most potently at TRPV2, moderately modulates TRPV3, TRPV4, TRPA1, and TRPM8, though Δ-THC is not reported to modulate TRPV1. Moreover, TRP receptors may modulate effects of synthetic cannabinoids used in research. One common research tool is WIN55,212-2, a CB1 agonist that also exerts analgesic effects by desensitizing TRPA1 and TRPV1. In this review article, we aim to provide an overview and classification of the cannabinoid ligands that have been reported to modulate TRP channels and their therapeutic potential.
Learn More >The University of Washington instituted a policy requiring all credentialed clinicians who prescribe opioids to complete a one-time education activity about safe and responsible opioid prescribing. A scenario-based, interactive online learning module was developed for opioid management of acute pain in hospitalized adults. This study examined the impact of the education module on learners' knowledge, perceived competence, and use of guideline-adherent practices.
Learn More >The study objectives were to identify baseline predictors of low back pain severity changes over a one-year period among patients attending multidisciplinary tertiary clinics and determine whether health care utilization impacts this outcome.
Learn More >The discovery of nociceptin/orphanin FQ (N/OFQ) marks the genuine start of the reverse pharmacology era, when systematic hunting for ligands of orphan receptors began. The choice of this particular target was no coincidence as the orphan receptor ORL-1 displayed high similarity to known opioid receptors, and thus its elusive ligand held promise to find more than a ligand but a missing opioid peptide. N/OFQ indeed turned out to belong to the opioid peptide family, but with significant pharmacological and functional distinctions. The quest for understanding N/OFQ's physiological functions has produced some novel insights into stress regulation and many other body functions but is still ongoing almost 25 years after its discovery. This chapter highlights the early steps of orphan receptor research and some of the protagonists who helped to advance the field.
Learn More >Previous studies have demonstrated important associations between personal resources and pain interference. Using latent profile analysis, the present study (a) identified subgroups of individuals with chronic pain who have different personal resource profiles; (b) explored sociodemographic differences among subgroups; and (c) examined how these subgroups differ in pain interference. Research Method/Design: Study 1 is based on daily diary and survey data from 220 individuals with fibromyalgia (FM). Study 2 is based on 4 annual surveys of 483 individuals with long-term neurological/neuromuscular disease or injury, and chronic pain. Modifiable personal resource variables including sense of resilience, social support, pain acceptance, and sleep quality were included in latent profile analyses.
Learn More >Early activation of transcription factors is one of the epigenetic mechanisms contributing to the induction and maintenance of chronic pain states. Previous studies identified the changes in a number of nociception-related genes, such as calcitonin gene-related peptide (CGRP), substance P (SP), and brain-derived neurotropic factor (BDNF) in the pelvic organs after transient colonic inflammation. The gene and protein expression of these neuropeptides could be modulated by transcription factors Methyl-CpG-binding protein 2 (Mecp2) and cAMP response element-binding protein (CREB). In this study, we aimed to evaluate time-dependent changes in the expression levels of Mecp2 and CREB in the lumbosacral (LS) spinal cord and sensory ganglia after inflammation-induced pelvic pain in rat. Adult Sprague-Dawley rats were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce transient colonic inflammation. LS (L6-S2) spinal cord segments and respective dorsal root ganglias (DRGs) were isolated from control and experimental animals at 1, 2, 6, 24 h and 3 days post-TNBS treatment. Immunohistochemical (IHC) labeling and Western blotting experiments were performed to assess the expression of Mecp2, CREB and their phosphorylated forms. Total Mecp2 expression, but not phosphorylated p-Mecp2 (pS421Mecp2) expression was detected in the cells of the spinal dorsal horn under control conditions. Colonic inflammation triggered a significant decrease in the number of Mecp2-expressing neurons in parallel with elevated numbers of pS421Mecp2-expressing cells at 2 h and 6 h post-TNBS. The majority of Mecp2-positive cells (80 ± 6%) co-expressed CREB. TNBS treatment caused a transient up-regulation of CREB-expressing cells at 1 h post-TNBS only. The number of cells expressing phosphorylated CREB (pS133CREB) did not change at 1 h and 2 h post-TNBS, but was down-regulated by three folds at 6 h post-TNBS. Analysis of DRG sections revealed that the number of Mecp2-positive neurons was up-regulated by TNBS treatment, reaching three-fold increase at 2 h post-TNBS, and eight-fold increase at 6 h post-TNBS ( ≤ 0.05 to control). These data showed early changes in Mecp2 and CREB expression in the dorsal horn of the spinal cord and sensory ganglia after colonic inflammation, suggesting a possible contribution Mecp2 and CREB signaling in the development of visceral hyperalgesia and pelvic pain following peripheral inflammation.
Learn More >Opioids are among the most effective and widely prescribed medications for the treatment of pain following spinal cord injury (SCI). Spinally-injured patients receive opioids within hours of arrival at the emergency room, and prolonged opioid regimens are often employed for the management of post-SCI chronic pain. However, previous studies in our laboratory suggest that the effects of opioids such as morphine may be altered in the pathophysiological context of neurotrauma. Specifically, we have shown that morphine administration in a rodent model of SCI increases mortality and tissue loss at the injury site, and decreases recovery of motor and sensory function, and overall health, even weeks after treatment. The literature suggests that opioids may produce these adverse effects by acting as endotoxins and increasing glial activation and inflammation. To better understand the effects of morphine following SCI, in this study we used flow cytometry to assess immune-competent cells at the lesion site. We observed a morphine-induced increase in the overall number of CD11b+ cells, with marked effects on microglia, in SCI subjects. Next, to investigate whether this increase in the inflammatory profile is necessary to produce morphine's effects, we challenged morphine treatment with minocycline. We found that pre-treatment with minocycline reduced the morphine-induced increase in microglia at the lesion site. More importantly, minocycline also blocked the adverse effects of morphine on recovery of function without disrupting the analgesic efficacy of this opioid. Together, our findings suggest that following SCI, morphine may exacerbate the inflammatory response, increasing cell death at the lesion site and negatively affecting functional recovery.
Learn More >The orphan nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammatory-related gene transcription in astroglioma cells, but their role in nociceptive transduction has yet to be elaborated. Spinal dorsal horn astrocytes contribute to the maintenance of chronic pain. Treatment of cultured spinal astrocytes with specific REV-ERBs agonists SR9009 or GSK4112 significantly prevented lipopolysaccharide (LPS)-induced mRNA upregulation of pronociceptive molecules interleukin-1β (IL-1β) mRNA, interleukin-6 (IL-6) mRNA and matrix metalloprotease-9 (MMP-9) mRNA, but not CCL2 mRNA expression. Treatment with SR9009 also blocked tumor necrosis factor-induced IL-1β mRNA, IL-6 mRNA and MMP-9 mRNA. In addition, treatment with SR9009 significantly blocked LPS-induced upregulation of IL-1β protein, IL-6 protein and MMP-9 activity. The inhibitory effects of SR9009 on LPS-induced expression of pronociceptive molecules were blocked by knockdown of REV-ERBs expression with short interference RNA, confirming that SR9009 exerts its effect through REV-ERBs. Intrathecal LPS treatment in male mice induces hind paw mechanical hypersensitivity, and upregulation of IL-1β mRNA, IL-6 mRNA and glial fibrillary acidic protein (GFAP) expression in spinal dorsal horn. Intrathecal pretreatment of SR9009 prevented the onset of LPS-induced mechanical hypersensitivity, cytokine expression and GFAP expression. Intrathecal injection of SR9009 also ameliorated mechanical hypersensitivity during the maintenance phase of complete Freund's adjuvant-induced inflammatory pain and partial sciatic nerve ligation-, paclitaxel-, and streptozotocin-induced neuropathy in mice. The current findings suggest that spinal astrocytic REV-ERBs could be critical in the regulation of nociceptive transduction through downregulation of pronociceptive molecule expression. Thus, spinal REV-ERBs could be an effective therapeutic target in the treatment of chronic pain.
Learn More >At our center in the Netherlands, patients, who very often are treatment resistant to the analgesics recommended in the guidelines, suffering from symmetrical peripheral neuropathic pain are treated exclusively. We have developed a number of compounded topical formulations containing classical co-analgesics such as ketamine, baclofen, amitriptyline, and phenytoin for the treatment of neuropathic pain in treatment-resistant patients. In order to identify putative responders and exclude an (initial) placebo-response, we developed single-blind and double-blind placebo-controlled response tests. The test can be performed when the patient has a symmetrical polyneuropathy with a pain score difference of not more than 1 point on the 11-point numerical rating scale (NRS) between bilateral pain areas. On one area (eg, left foot) the placebo cream and on the other area (eg, right foot) the active cream will be applied. Within a time frame of 30 minutes, patients are considered responders if they rate a pain difference of at least 2 points on the NRS between the bilateral areas on which the active cream and placebo cream are applied. Response tests can be easily conducted during the first consultation. In this paper, we explore the ethical context of using a placebo in clinical practice in a single-blind and double-blind fashion to improve and individualize treatment of neuropathic pain outside a context of a formal clinical trial.
Learn More >Inhibition of the NGF/TrkA interaction presents an interesting alternative to the use of non-steroidal anti-inflammatories and/or opioids for the control of inflammatory, chronic and neuropathic pain. Most prominent of the current approaches to this therapy is the antibody Tanezumab, which is a late-stage development humanized monoclonal antibody that targets NGF. We sought to determine whether peptides might similarly inhibit the NGF/TrkA interaction and so serve as future therapeutic leads. Starting from two peptides that inhibit the NGF/TrkA interaction, we sought to eliminate a cysteine residue close to the C-terminal of both sequences, by an approach of mutagenic analysis and saturation mutagenesis of mutable residues. Elimination of cysteine from a therapeutic lead is desirable to circumvent manufacturing difficulties resulting from oxidation. Our analyses determined that the cysteine residue is not required for NGF binding, but is essential for inhibition of the NGF/TrkA interaction at pharmacologically relevant peptide concentrations. We conclude that a cysteine residue is required within potential peptide-based therapeutic leads and hypothesise that these peptides likely act as dimers, mirroring the dimeric structure of the TrkA receptor.
Learn More >To assess conditioned pain modulation efficiency in persons with and without migraine headaches.
Learn More >To determine the association of medical marijuana legalization with prescription opioid utilization.
Learn More >Descending nociceptive modulation from the supraspinal structures has an important role in cancer-induced bone pain (CIBP). Midbrain ventrolateral periaqueductal gray (vlPAG) is a critical component of descending nociceptive circuits; nevertheless, its precise cellular and molecular mechanisms involved in descending facilitation remain elusive. Our previous study has shown that activation of p38 MAPK in vlPAG microglia is essential for the neuropathic pain sensitization. However, the existence of potential connection between astrocytes and JNK pathway in CIBP has not yet been elucidated. The following study examines the involvement of astrocyte activation and up-regulation of p-JNK in vlPAG, using a CIBP rat model. Briefly, CIBP was mimicked by an intramedullary injection of Walker 256 mammary gland carcinoma cells into the animal tibia. A significant increase in expression levels of astrocytes in the vlPAG of CIBP rats was observed. Furthermore, stereotaxic microinjection of the astrocytic cytotoxin L-α-aminoadipic acid decreased the mechanical allodynia, as well as established and reversed the astrocyte activation in CIBP rats. A significant increase in expression levels of p-JNK in astrocytes in vlPAG of CIBP rats was also observed. Moreover, the intrathecal administration of JNK inhibitors SP600125 reduced the expression of GFAP, while microinjection of the SP600125 decreased the mechanical allodynia of CIBP rats. These results suggested that cancer-induced bone pain is associated with astrocyte activation in the vlPAG that probably participates in driving descending pain facilitation through the JNK MAPK signaling pathway. To sum up, these findings reveal a novel site of astrocytes modulation of CIBP.
Learn More >To understand the efficacy of zolmitriptan applied with Adhesive Dermally Applied Microarray (ADAM) in treating types of migraine (those with severe headache pain, the presence of nausea, treatment ≥2 hours after migraine onset, or migraine present upon awakening) that are historically considered to be less responsive to oral medications.
Learn More >This article presents the results of a parallel-group, non-randomized, controlled study that evaluated the feasibility of an online training program for improving observer detection of facial pain expression.
Learn More >Increasing evidence indicates that pattern recognition receptors (PRRs) are involved in neuropathic pain after peripheral nerve injury (PNI). While a significant number of studies support an association between neuropathic pain and the innate immune response mediated through Toll-like receptors, a family of PRRs, the roles of other types of PRRs are largely unknown. In this study, we have focused on the macrophage-inducible C-type lectin (Mincle), a PRR allocated to the C-type lectin receptor family. Here, we show that Mincle is involved in neuropathic pain after PNI. Mincle-deficient mice showed impaired PNI-induced mechanical allodynia. After PNI, expression of Mincle mRNA was rapidly increased in the injured spinal nerve. Most Mincle-expressing cells were identified as infiltrating leucocytes, although the migration of leucocytes was also observed in Mincle-deficient mice. Furthermore, Mincle-deficiency affected the induction of genes, which are reported to contribute to neuropathic pain after PNI in the dorsal root ganglia and spinal dorsal horn. These results suggest that Mincle is involved in triggering sequential processes that lead to the pathogenesis of neuropathic pain.
Learn More >Individuals with chronic pain who misuse prescription opioids are at high risk for developing opioid use disorder and/or succumbing to opioid overdose. The current study conducted a survey to evaluate sex-based differences in pain catastrophizing, opioid withdrawal, and current pain in persons with co-occurring chronic pain and opioid misuse. We hypothesized that women with chronic pain who misused prescription opioids would self-report higher pain ratings compared with men and that the relationship between pain catastrophizing and self-reported current pain would be moderated by symptoms of opioid withdrawal in women only.
Learn More >Dental pain is a common health problem that negatively impacts the activities of daily living. Dentine hypersensitivity and pulpitis-associated pain are among the most common types of dental pain. Patients with these conditions feel pain upon exposure of the affected tooth to various external stimuli. However, the molecular mechanisms underlying dental pain, especially the transduction of external stimuli to electrical signals in the nerve, remain unclear. Numerous ion channels and receptors localized in the dental primary afferent neurons (DPAs) and odontoblasts have been implicated in the transduction of dental pain, and functional expression of various polymodal transient receptor potential (TRP) channels has been detected in DPAs and odontoblasts. External stimuli-induced dentinal tubular fluid movement can activate TRP channels on DPAs and odontoblasts. The odontoblasts can in turn activate the DPAs by paracrine signaling through ATP and glutamate release. In pulpitis, inflammatory mediators may sensitize the DPAs. They could also induce post-translational modifications of TRP channels, increase trafficking of these channels to nerve terminals, and increase the sensitivity of these channels to stimuli. Additionally, in caries-induced pulpitis, bacterial products can directly activate TRP channels on DPAs. In this review, we provide an overview of the TRP channels expressed in the various tooth structures, and we discuss their involvement in the development of dental pain.
Learn More >Previous findings have demonstrated that torture survivors exhibit chronic pain and alterations in pain perception. However, not much is known regarding the characteristics of the torture experience and its contribution to these long-term ramifications. The current study examined the unique role of objective severity and subjective suffering in torture in predicting chronic pain and acute pain perception and pain modulation.
Learn More >Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K 1.1 mRNA and its coding K 1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel-induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K 1.1 and mimicking this increase reduces DRG K 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K 1.1 may contribute to chemotherapy-induced neuropathic pain. This article is protected by copyright. All rights reserved.
Learn More >There has been great development in the testing of invasive and non-invasive neuromodulation for chronic pain. To date, it is known that central and peripheral stimulation targets, combined or not, may influence chronic pain sensation. Although most of the significant results of chronic pain studies come from motor cortex stimulation, novel targets are being explored to increase effect sizes and to induce pain relief in non-responders. Areas covered: In this article, we discuss three emerging targets of non-invasive neuromodulation for chronic pain: (i) a central target: prefrontal cortex stimulation; (ii) a peripheral target: vagal nerve stimulation (VNS); and (iii) a combined peripheral-central target: combination of central and peripheral neural stimulation. Expert commentary: Clinical trials' results on novel targets for chronic pain are at an earlier stage and the mechanisms involved with their combination remain unclear. An important challenge to validate new targets is to determine whether they may be equivalent or even more effective than traditional ones. In spite of the significant advance in this field, especially in refractory chronic pain, mechanistic elements are yet to be comprehended. Thus, exploring multifactorial aspects of novel brain stimulation approaches is fundamental to achieve meaningful results and further augment clinical practice.
Learn More >Skin denervation that develops in patients with diabetes mellitus as a neuropathic manifestation is known as diabetic peripheral neuropathy (DPN). Skin denervation is parallel to neuronal injuries that alter intracellular signaling. To date, the correlation between nerve injury and the activation of intracellular responses to neuropathic manifestations has not been elucidated; specifically, whether activating transcription factor 3 (ATF3) is responsible for neuronal injury and a critical molecule that modulates the activation of intracellular protein kinase C epsilon (p-PKCε) and pain development in DPN is a crucial question.
Learn More >Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate rhythmic electrical activity of cardiac pacemaker cells, and in neurons play important roles in setting resting membrane potentials, dendritic integration, neuronal pacemaking, and establishing action potential threshold. Block of HCN channels slows the heart rate and is currently used to treat angina. However, HCN block also provides a promising approach to the treatment of neuronal disorders including epilepsy and neuropathic pain. While several molecules that block HCN channels have been identified, including clonidine and its derivative alinidine, lidocaine, mepivacaine, bupivacaine, ZD7288, ivabradine, zatebradine, and cilobradine, their low affinity and lack of specificity prevents wide-spread use. Different studies suggest that the binding sites of these inhibitors are located in the inner vestibule of HCN channels, but the molecular details of their binding remain unknown. We used computational docking experiments to assess the binding sites and mode of binding of these inhibitors against the recently solved atomic structure of human HCN1 channels, and a homology model of the open pore derived from a closely related CNG channel. We identify a possible hydrophobic groove in the pore cavity that plays an important role in conformationally restricting the location and orientation of drugs bound to the inner vestibule. Our results also help explain the molecular basis of the low-affinity binding of these inhibitors, paving the way for the development of higher affinity molecules.
Learn More >Background and aims Chronic pelvic pain (CPP) in women is a complex condition that can seriously impact health and quality of life. Clinical guidelines for CPP place great demands on healthcare professionals, as they require both specialized knowledge about the pelvic area and knowledge of the mechanisms of chronic pain. To ensure best possible assessment and treatment of these women it is important to bring about more knowledge of the special CPP features. The purpose of this paper is to describe the characteristics of women with CPP evaluated at the University Hospital of North Norway, and further referred to physiotherapy. The frequency of having a history of abuse or previous pelvic surgery will also be reported, and analyses performed to investigate if subjective health status differs between women with and without these experiences. Methods We collected cross-sectional data from 62 women with CPP aged 20-65 (mean age 38.0), referred to physiotherapy after assessment by medical specialists. Data were collected by semi-structured interviews for demographic variables and medical history, and self-administered questionnaires on pain intensity, sexual function, urinary incontinence (UI), anal incontinence (AI), obstructed defecation syndrome (ODS), subjective health complaints (SHC) and symptoms of anxiety and depression. Results Pain duration of more than 10 years was reported by 42%, mean pain score was 4.7/10, and analgesics were used weekly by 48%. Previous pelvic or abdominal surgery was reported by 71%, and sick leave >12 weeks the last year by 34%. Reduced sexual desire was reported by 78%, dyspareunia by 73%, UI by 54%, AI by 23%, and obstructed defecation syndrome (ODS) by 34%. More than 90% reported musculoskeletal or pseudoneurologic complaints. Anxiety and depression scores defined as requiring treatment were reported by 40%. Abuse was reported by 50%, and associated with significantly more reports of ODS (p=0.02), more SHC (p=0.02) and higher anxiety scores (p=0.009). Analgesic use and sick leave were significantly higher both among women with a history of abuse (p=0.04 and p=0.005) and among those with previous surgery (p=0.04 and p=0.02). Women with previous surgery reported significantly lower pain intensity during intercourse than those without previous surgery (p=0.008). Conclusions Women with CPP have complex symptoms and high scores for both physical and psychological complaints. Women exposed to abuse have especially high scores related to analgesic use, sick leave, ODS, anxiety and SHC. Women with previous surgery report more analgesic use and sick leave, and lower pain intensity during intercourse, than those without previous surgery. Implications This study illustrates the complexity of CPP and highlights the need for health professionals to have specialized knowledge of the possible features of the condition. Previous abuse seems to be more associated with poor scores on several health outcomes than surgery, but this needs to be investigated further.
Learn More >The experience of chronic non-cancer pain (CNCP) is one of the most common reasons individuals seek medical attention. Patients with CNCP frequently experience concomitant sleep-related problems.
Learn More >Use of prescription opioids and problems of abuse and addiction have increased over the past decade. Claims-based studies have documented substantial economic burden of opioid abuse. This study utilized electronic health record (EHR) data to identify chronic opioid therapy (COT) patients with problem opioid use (POU) and compared costs with those for COT patients without POU. This study utilized EHR and claims data from an integrated health care system. Patients received COT (≥70 days' supply in ≥1 calendar quarter, 2006-2012). Natural language processing (NLP) identified notations of opioid addiction, abuse, misuse, or overuse, and manual validation was performed. Cases had evidence of POU (index = first POU notation), and controls, sampled 9:1, did not. Health care resource utilization was measured and costs estimated using Medicare reimbursement rates. A longitudinal analysis of costs was conducted using generalized estimating equations. Adjusted analyses controlled for baseline age, gender, region, specific comorbidities, and a comorbidity index. The analysis population included 1,125 cases and 10,128 controls. Unadjusted costs were higher for cases in all three years. After controlling for covariates, total costs remained higher in cases and were significantly higher in the first year of follow-up ($38,064 vs. $31,674, P = .0048). The largest cost difference was observed in the first month of follow-up. COT patients with POU experienced significantly higher costs compared with COT patients without POU in the first year of follow-up. The greatest difference in costs was observed around identification of POU.
Learn More >Low back pain (LBP) is the most prevalent musculoskeletal problem among adults. Individuals with chronic LBP (CLBP) can present a psychological disorder and a lack of pain self-efficacy.
Learn More >Fibromyalgia (FM) is a chronic illness characterised by the presence of generalised musculoskeletal pain among other symptoms, which reduce the quality of life of the patient. Clinical interventions such as patient education on central pain management could lead to promising results. The aim of this study is to evaluate the effectiveness of education techniques on the main symptoms such as pain, quality of life, anxiety, functionality or catastrophisation in the treatment of FM.
Learn More >Chronic pain is a common public health problem that has a detrimental impact on patient health, quality of life (QoL), and function, and poses a substantial socioeconomic burden. Evidence supports redefinition of chronic pain as a distinct disease entity, not simply a symptom of injury or illness. Chronic pain conditions are characterized by three types of pain pathophysiology – i.e., nociceptive, neuropathic, and centralized pain/central sensitization -influenced by a cluster of coexisting psychosocial factors. Negative risk/vulnerability factors, e.g., mood or sleep disturbances, and positive resilience/protective factors, e.g., social/interpersonal relationships and active coping, interact with pain neurobiology to determine patients' unique pain experience. Viewing chronic pain through a biopsychosocial lens, instead of a purely biomedical one, clinicians need to adopt a practical integrated management approach. Thorough assessment focuses on the whole patient (not just the pain), including comorbidities, cognitive/emotional/behavioral characteristics, social environment, and QoL/functional impairment. As for other complex chronic illnesses, the treatment plan for chronic pain can be developed based on pain subtype and psychosocial profile, incorporating pharmacotherapy and self-management modalities. Preferred pharmacologic treatment of conditions primarily associated with nociception (e.g., osteoarthritis) includes acetaminophen and non-steroidal anti-inflammatory drugs, whereas preferred pharmacologic treatment of conditions primarily associated with neuropathy or central sensitization (e.g., fibromyalgia) includes tricyclic compounds, serotonin norepinephrine reuptake inhibitors, and αδ ligands. Education, exercise, cognitive behavioral therapy, and many other non-pharmacological approaches, alone or combined with pharmacotherapy, have been shown to be effective for any type of pain, although they remain underutilized due to lack of awareness of their benefits and reimbursement obstacles.
Learn More >The development of opioid-induced analgesic tolerance is a clinical challenge in long-term use for managing chronic pain. The mechanisms of morphine tolerance are poorly understood. Mitochondria-derived reactive oxygen species (ROS) is a crucial signal inducing analgesic tolerance and pain. Chronic administration of morphine leads to robust ROS production and accumulation of damaged mitochondria, which are immediately removed by mitophagy. Here, we show that morphine inhibits mitochondria damage-induced accumulation of PTEN-induced putative kinase 1 (PINK1) in neurons. It interrupts the recruitment of Parkin to the impaired mitochondria and inhibits the ubiquitination of mitochondrial proteins catalyzed by Parkin. Consequently, morphine suppresses the recognition of autophagosomes to the damaged mitochondria mediated by LC3 and SQSTM1/p62 (sequestosome-1). Thus, morphine inhibits autophagy flux and leads to the accumulation of SQSTM1/p62. Finally, the impaired mitochondria cannot be delivered to lysosomes for degradation and ultimately induces robust ROS production and morphine tolerance. Our findings suggest that the dysfunction of mitophagy is involved in morphine tolerance. The deficiency of PINK1/Parkin-mediated clearance of damaged mitochondria is crucial for the generation of excessive ROS and important to the development of analgesic tolerance. These findings suggest that the compounds capable of stabilizing PINK1 or restoring mitophagy may be utilized to prevent or reduce opioid tolerance during chronic pain management.
Learn More >Most patients with migraine report associated neck pain. Whether neck pain is a symptom of migraine or an indicator for associated cervical musculoskeletal impairment has not yet been determined. Physical examination tests to detect cervical impairments in people with headache have been suggested, but results have not been evaluated systematically and combined in meta-analyses.
Learn More >Chronic pain affects a significant proportion of the population and presents a major challenge to clinicians and pain specialists. Despite the availability of pharmacologic treatment options such as opioids, many patients continue to experience persistent pain. Cannabinoids present an alternative option with some data on efficacy; however, to date, a systematic review of adverse events (AEs) assessment and reporting in randomized clinical trials (RCTs) involving cannabinoids has not been performed. As a result, it is unclear whether a clear profile of cannabinoid-associated AEs has been accurately detailed in the literature. As cannabinoids are likely to become readily available for patients in the near future, it is important to study how well AEs have been reported in trials so that the safety profile of cannabinoids can be better understood.
Learn More >P2X4 and P2X7 receptors play an important role in neuropathic pain after spinal cord injury. Regulation of P2X4 and P2X7 receptors can obviously reduce pain hypersensitivity after injury. To investigate the role of neural stem cell transplantation on P2X receptor-mediated neuropathic pain and explore related mechanisms, a rat model of spinal cord injury was prepared using the free-falling heavy body method with spinal cord segment 10 as the center. Neural stem cells were injected into the injured spinal cord segment using a micro-syringe. Expression levels of P2X4 and P2X7 receptors, neurofilament protein, and glial fibrillary acidic protein were determined by immunohistochemistry and western blot assay. In addition, sensory function was quantitatively assessed by current perception threshold. The Basso-Beattie-Bresnahan locomotor rating scale was used to assess neuropathological pain. The results showed that 4 weeks after neural stem cell transplantation, expression of neurofilament protein in the injured segment was markedly increased, while expression of glial fibrillary acidic protein and P2X4 and P2X7 receptors was decreased. At this time point, motor and sensory functions of rats were obviously improved, and neuropathic pain was alleviated. These findings demonstrated that neural stem cell transplantation reduced overexpression of P2X4 and P2X7 receptors, activated locomotor and sensory function reconstruction, and played an important role in neuropathic pain regulation after spinal cord injury. Therefore, neural stem cell transplantation is one potential option for relieving neuropathic pain mediated by P2X receptors.
Learn More >To characterize the impacts of policies intended to improve opioid prescribing and prevent opioid-related overdose and death on individuals who take opioids.
Learn More >Pain is one of the cardinal signs of inflammation and is present in many inflammatory conditions. Therefore, anti-inflammatory drugs such as NSAIDs also have analgesic properties. We previously showed that prostaglandin D-glycerol ester (PGD-G), endogenously produced by cyclooxygenase-2 from the endocannabinoid 2-arachidonoylglycerol, has anti-inflammatory effects in vitro and in vivo that are partly mediated by DP1 receptor activation. In this work, we investigated its effect in a model of carrageenan-induced inflammatory pain. PGD-G decreased hyperalgesia and edema, leading to a faster recovery. Moreover, PGD-G decreased carrageenan-induced inflammatory markers in the paw as well as inflammatory cell recruitment. The effects of PGD-G were independent from metabolite formation (PGD and 15d-PGJ-G) or DP1 receptor activation in this model. Indeed PGD delayed recovery from hyperalgesia while 15d-PGJ-G worsened the edema. However, while PGD-G decreased hyperalgesia in this model of inflammatory pain, it had no effect when tested in the capsaicin-induced pain model. While the targets mediating the effects of this bioactive lipid in inflammatory pain remain to be elucidated, our findings further support the interest of anti-inflammatory lipid mediators in the management of inflammatory pain.
Learn More >Although psychosocial evaluations for implantable pain devices have been consensus recommendations since the 1990's, there is an inconsistent support regarding their ability to identify suitable pain device candidates or to predict clinical outcomes. With the emergence of evidence-based practices and the recent release of pain management guidelines emphasizing functional improvements and safety, the disparity between the recommendations for implantable pain device psychosocial evaluations and the evidence supporting them has only grown. In this special report, we describe a revised model for conducting psychosocial evaluations among implantable pain device candidates. This model includes changes to increase the evidence-basis of the psychosocial evaluations, incorporate patient-centered care standards and harmonize the evaluation structure with the most current pain management guidelines.
Learn More >