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Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1-/-) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1-/- mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1-/- mice. Consistently, these beneficial effects in Pd1-/- mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.
Learn More >Sodium channel Nav1.7, encoded by the SCN9A gene, is a well-validated target that plays a key role in controlling pain sensation. Loss-of-function mutations of Nav1.7 can cause a syndrome of profound congenital insensitivity to pain in humans. Better understanding of how the loss of Nav1.7 leads to loss of pain sensibility would help to decipher the fundamental mechanisms of nociception and inform strategies for development of novel analgesics. Using a recently described rat Nav1.7 loss-of-function model with deficient nociception but intact olfactory function, we investigated the involvement of endogenous opioid and cannabinoid systems in this rodent model of Nav1.7-related congenital insensitivity to pain. We found that both the opioid receptor antagonist naloxone and cannabinoid receptor blockers SR141716A (rimonabant) and SR144528 fail to restore acute pain sensitivity in Nav1.7 loss-of-function rats. We observed, however, that after rimonabant administration, Nav1.7 loss-of-function but not WT rats displayed abnormal behaviours, such as enhanced scratching, caudal self-biting, and altered facial expressions; the underlying mechanism is still unclear. Dorsal root ganglion neurons from Nav1.7 loss-of-function rats, although hypoexcitable compared with WT neurons, were still able to generate action potentials in response to noxious heat and capsaicin. Our data indicate that complete loss of dorsal root ganglion neuron excitability is not required for insensitivity to pain and suggest that endogenous opioid and cannabinoid systems are not required for insensitivity to pain in the absence of Nav1.7 channels in this rat Nav1.7 loss-of-function model.
Learn More >Fast purinergic signaling is mediated by ATP and ATP-gated ionotropic P2X receptors (P2XRs), and it is implicated in pain-related behaviors. The properties exhibited by P2XRs vary between those expressed in heterologous cells and in vivo. Several modulators of ligand-gated ion channels have recently been identified, suggesting that there are P2XR functional modulators in vivo. Here, we establish a genome-wide open reading frame (ORF) collection and perform functional screening to identify modulators of P2XR activity. We identify TMEM163, which specifically modulates the channel properties and pharmacology of P2XRs. We also find that TMEM163 is required for full function of the neuronal P2XR and a pain-related ATP-evoked behavior. These results establish TMEM163 as a critical modulator of P2XRs in vivo and a potential target for the discovery of drugs for treating pain.
Learn More >Chronic pain is a significant health problem worldwide with limited pharmacological treatment options. This study evaluated the relative efficacy of four treatment sessions each of four non-pharmacological treatments: (1) hypnotic cognitive therapy (using hypnosis to alter the meaning of pain); (2) standard cognitive therapy; (3) hypnosis focused on pain reduction, and (4) pain education. One hundred seventy-three individuals with chronic pain were randomly assigned to receive four sessions of one of the four treatments. Primary (pain intensity) and secondary outcome measures were administered by assessors unaware of treatment allocation at pre-treatment, post-treatment, and 3-, 6- and 12-month follow-up. Treatment effects were evaluated using ANOVA, a generalized estimating equation approach, or a Fisher Exact Test, depending on the outcome domain examined. All four treatments were associated with medium to large effect size improvements in pain intensity that maintained up to 12 months post-treatment. Pre- to post-treatment improvements were observed across the four treatment conditions on the secondary outcomes of pain interference and depressive symptoms, with some return towards pre-treatment levels at 12-months follow-up. No significant between group differences emerged in omnibus analyses, and few statistically significant between-group differences emerged in the planned pairwise analyses, although the two significant effects that did emerge favored hypnotic cognitive therapy. Future research is needed to determine if the significant differences that emerged are reliable.
Learn More >Classical Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder caused by heterozygous mutations in one of the type V collagen-encoding genes, COL5A1 or COL5A2. cEDS is characterized by generalized joint hypermobility and instability, hyperextensible, fragile skin and delayed wound healing. Chronic pain is a major problem in cEDS patients, but the underlying mechanisms are largely unknown, and studies in animal models are lacking. Therefore, we assessed pain-related behaviors in haploinsufficient Col5a1 mice, which clinically mimic human cEDS. Compared to wild-type (WT) littermates, 15-20 week-old Col5a1 mice of both sexes showed significant hypersensitivity to mechanical stimuli in the hind paws and the abdominal area, but responses to thermal stimuli were unaltered. Spontaneous behaviors, including distance travelled and rearing, were grossly normal in male Col5a1 mice, while female Col5a1 mice showed altered climbing behavior. Finally, male and female Col5a1 mice vocalized more than WT littermates when scruffed. Decreased grip strength was also noted. In view of the observed pain phenotype Col5a1 mice were crossed with NaV1.8-tdTomato reporter mice, enabling visualization of nociceptors in the glabrous skin of the footpad. We observed a significant decrease in intra-epidermal nerve fiber density, with fewer nerves crossing the epidermis, and a decreased total nerve length of Col5a1 mice compared to WT. In summary, male and female Col5a1 mice show hypersensitivity to mechanical stimuli, indicative of generalized sensitization of the nervous system, in conjunction with an aberrant organization of cutaneous nociceptors. Therefore, Col5a1 mice will provide a useful tool to study mechanisms of pain associated with cEDS.
Learn More >Regulators of G protein signaling (RGS) are multifunctional proteins expressed in peripheral and neuronal cells, playing critical roles in development, physiological processes, and pharmacological responses. RGS proteins primarily act as GTPase accelerators for activated Gα subunits of G-protein coupled receptors (GPCRs), but they may also modulate signal transduction by several other mechanisms. Over the last two decades, preclinical work identified members of the RGS family with unique and critical roles in intracellular responses to drugs of abuse. New information has emerged on the mechanisms by which RGS proteins modulate the efficacy of opioid analgesics in a brain region- and agonist-selective fashion. There has also been progress in the understanding of the protein complexes and signal transduction pathways regulated by RGS proteins in addiction and analgesia circuits. In this review, we summarize findings on the mechanisms by which RGS proteins modulate functional responses to opioids in models of analgesia and addiction. We also discuss reports on the regulation and function of RGS proteins in models of psychostimulant addiction. Using information from preclinical studies performed over the last 20 years, we highlight the diverse mechanisms by which RGS protein complexes control plasticity in response to opioid and psychostimulant drug exposure; we further discuss how the understanding of these pathways may lead to new opportunities for therapeutic interventions in G protein pathways SIGNIFICANCE STATEMENT: RGS proteins are signal transduction modulators, expressed widely in various tissues, including brain regions mediating addiction and analgesia. Evidence from preclinical work suggests that members of the RGS family act by unique mechanisms in specific brain regions to control drug-induced plasticity. This review highlights interesting findings on the regulation and function of RGS proteins in models of analgesia and addiction.
Learn More >Dopaminergic symptoms may be extremely pronounced in some migraine patients during the attack, representing a major source of disability.
Learn More >Recent clinical findings suggest that oxytocin could be a novel treatment for migraine. However, little is known about the role of this neuropeptide/hormone and its receptor in the trigeminovascular pathway. Here we determine expression, localization, and function of oxytocin and oxytocin receptors in rat trigeminal ganglia and targets of peripheral (dura mater and cranial arteries) and central (trigeminal nucleus caudalis) afferents.
Learn More >Cortical spreading depression is thought to be the underlying mechanism of migraine aura. In 2006, three relatives having the point mutation E700K in exon 15 were diagnosed with familial hemiplegic migraine 2 characterized by complicated forms of aura. Here, we generated a transgenic mouse model having the human E700K mutation in the orthologous gene.
Learn More >Painful diabetic polyneuropathy (DPN) is difficult to manage as treatment response is often varied. The primary aim of this study was to examine differences in pain phenotypes between responders and non-responders to intravenous lidocaine treatment using quantitative sensory testing. The secondary aim was to explore differences in brain structure and functional connectivity with treatment response. Forty-five consecutive patients who received intravenous lidocaine treatment for painful DPN were screened. Twenty-nine patients who met the eligibility criteria (responders n=14 and non-responders n=15) and 26 healthy controls underwent detailed sensory profiling. Subjects also underwent multimodal brain magnetic resonance (MR) imaging. Greater proportion of patients with the irritable (IR) nociceptor phenotype were responders to intravenous lidocaine treatment compared to non-responders . The odd-ratio of responding to intravenous lidocaine was 8.67 times greater (95%CI 1.4:53.8) for the IR nociceptor phenotype. Responders to intravenous lidocaine also had significantly greater mean S1 cortical volume and functional connectivity between the insula cortex and the corticolimbic circuitry. This study provides preliminary evidence for a mechanism-based approach for individualising therapy in patients with painful DPN.
Learn More >Naked mole-rats () have adaptations within their pain pathway that are beneficial to survival in large colonies within poorly ventilated burrow systems, with lower O and higher CO ambient levels than ground-level environments. These adaptations ultimately lead to a partial disruption of the C-fiber pain pathway, which enables naked mole-rats to not feel pain from the acidosis associated with CO accumulation. One hallmark of this disruption is that naked mole-rats do not express neuropeptides, such as Substance P and calcitonin gene-related peptide in their cutaneous C-fibers, effectively making the peptidergic pain pathway hypofunctional. One C-fiber pathway that remains unstudied in the naked mole-rat is the non-peptidergic, purinergic pathway, despite this being a key pathway for inflammatory pain. The current study aimed to establish the functionality of the purinergic pathway in naked mole-rats and the effectiveness of cannabinoids in attenuating pain through this pathway. Cannabinoids can manage chronic inflammatory pain in both humans and mouse models, and studies suggest a major downstream role for the purinergic receptor, P2X3, in this treatment. Here we used Ca-imaging of cultured dorsal root ganglion neurons and behavioral testing to demonstrate that the P2X3 pathway is functional in naked mole-rats. Additionally, formalin-induced inflammatory pain was reduced by the cannabinoid receptor agonist, WIN55 (inflammatory, but not acute phase) and the P2X3 receptor antagonist A-317491 (acute and inflammatory phases). This study establishes that the purinergic C-fiber pathway is present and functional in naked mole-rats and that cannabinoid-mediated analgesia occurs in this species.
Learn More >Patients suffering with functional somatic pain syndromes such as temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) have some similar symptoms, but the underlying cause is still unclear. The purpose of this study was to investigate whether 5-HT and 5-HT receptors in the spinal cord contribute to somatic hyperalgesia induced by orofacial inflammation combined with different modes of stress. Ovariectomized rats were injected subcutaneously with estradiol and bilateral masseter muscles were injected with complete Freund's adjuvant followed by stress. Somatic sensitivity was assessed with thermal and mechanical stimulation. The anxiety- and depression-like behaviors were measured by immobility time, sucrose preference, elevated plus maze and open field tests. The expression of 5-HT and 5-HT receptors in the spinal cord was examined by western blot. Orofacial inflammation combined with 11 day forced swim stress (FSS) induced persistent mechanical allodynia for 15 days and thermal hyperalgesia for 2 days. The mechanical and thermal hyperalgesia lasted for 43 days and 30 days respectively following orofacial inflammation combined with 11 day heterotypic stress. Orofacial inflammation combined with stress induced anxiety- and depression-like behaviors. The expression of 5-HT and 5-HT receptors significantly decreased in the orofacial inflammation combined with stress groups. Intrathecal injection of 5-HT or 5-HT receptor agonist reversed somatic hyperalgesia. The results suggest that down-regulation of 5-HT and 5-HT receptors in the spinal cord contributes to somatic hyperalgesia induced by orofacial inflammation combined with stress, indicating that 5-HT and 5-HT receptors may be potential targets in the treatment of TMD comorbid with FMS.
Learn More >Chronic pruritus, or itch lasting >6 weeks, is a common symptom and has a profoundly negative impact on quality of life. While many primary dermatologic disorders such as atopic dermatitis and chronic urticaria are characterized by pruritus, numerous other allergic, hepatobiliary, lymphoproliferative, neurologic, and renal disorders are associated with chronic pruritus. Itch involves complex interactions orchestrated by a variety of factors released from and acting on the skin, immune system, and the sensory nervous system. This review summarizes recent therapeutic developments for chronic pruritus with a focus on allergic and type 2 inflammatory pathways.
Learn More >Many clinical trials fail because of placebo responses. Prior therapeutic experiences and patients' expectations may affect the capacity to respond to placebos in chronic disorders.
Learn More >Abrocitinib, an oral, once-daily Janus kinase 1 selective inhibitor, was effective and well tolerated in a phase 3 monotherapy trial of patients with moderate-to-severe atopic dermatitis (AD).
Learn More >Oxaliplatin is a commonly used drug to treat cancer, extending the rate of disease-free survival by 20% in colorectal cancer. However, oxaliplatin induces a disabling form of neuropathy resulting in more than 60% of patients having to reduce or discontinue oxaliplatin, negatively impacting their chance of survival. Oxaliplatin-induced neuropathies are accompanied by degeneration of sensory fibers in the epidermis and hyperexcitability of sensory neurons. These morphological and functional changes have been associated with sensory symptoms such as dysesthesia, paresthesia and mechanical and cold allodynia. Various strategies have been proposed to prevent or treat oxaliplatin-induced neuropathies without success. The anti-diabetic drug metformin has been recently shown to exert neuroprotection in other chemotherapy-induced neuropathies, so here we aimed to test if metformin can prevent the development of oxaliplatin-induced neuropathy in a rat model of this condition. Animals treated with oxaliplatin developed significant intraepidermal fiber degeneration, a mild gliosis in the spinal cord, and mechanical and cold hyperalgesia. The concomitant use of metformin prevented degeneration of intraepidermal fibers, gliosis, and the altered sensitivity. Our evidence further supports metformin as a new approach to prevent oxaliplatin-induced neuropathy with a potential important clinical impact.
Learn More >The purpose of this study is to determine the association between presence of chronic pain and school functioning among school aged children (6-17▒y) using the most recent United States national data.
Learn More >Irritable bowel syndrome (IBS) is a disorder involving dysfunctional brain-gut interactions characterized by chronic recurrent abdominal pain, altered bowel habits, and negative emotion. Previous studies have linked the habenula to the pathophysiology of negative emotion and pain. However, no studies to date have investigated habenular function in IBS patients. In this study, we investigated the resting-state functional connectivity (rsFC) and effective connectivity of the habenula in 34 subjects with IBS and 34 healthy controls and assessed the feasibility of differentiating IBS patients from healthy controls using a machine learning method. Our results showed significantly enhanced rsFC of the habenula-left dorsolateral prefrontal cortex (dlPFC) and habenula-periaqueductal grey (PAG, dorsomedial part), as well as decreased rsFC of the habenula-right thalamus (dorsolateral part), in the IBS patients compared with the healthy controls. Habenula-thalamus rsFC was positively correlated with pain intensity (r = .467, p = .005). Dynamic causal modeling (DCM) revealed significantly decreased effective connectivity from the right habenula to the right thalamus in the IBS patients compared to the healthy controls that was negatively correlated with disease duration (r = -.407, p = .017). In addition, IBS was classified with an accuracy of 71.5% based on the rsFC of the habenula-dlPFC, habenula-thalamus, and habenula-PAG in a support vector machine (SVM), which was further validated in an independent cohort of subjects (N = 44, accuracy = 65.2%, p = .026). Taken together, these findings establish altered habenular rsFC and effective connectivity in IBS, which extends our mechanistic understanding of the habenula's role in IBS.
Learn More >The present study examined pre- to post-treatment changes in volumes for brain structures known to be associated with pain processing (thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and accumbens) following an interdisciplinary pain management program.
Learn More >Quantitative sensory testing protocols for perceptions of pleasantness and unpleasantness based on the German Research Network on Neuropathic Pain protocol were recently introduced. However, there are no reliability studies yet published.
Learn More >Several neurotransmitters are expressed in the neurons of the trigeminal ganglion. One such signalling molecule is the pituitary adenylate cyclase-activating peptide (PACAP). PACAP signalling has been suggested to have a possible role in the pathophysiology of primary headaches.
Learn More >In the mid-1970s, an intense race to identify endogenous substances that activated the same receptors as opiates resulted in the identification of the first endogenous opioid peptides. Since then, ~20 peptides with opioid receptor activity have been discovered, all of which are generated from three precursors (proenkephalin, prodynorphin, and proopiomelanocortin) by sequential proteolytic processing by prohormone convertases and carboxypeptidase E. Each of these peptides bind to all three of the opioid receptor types (mu, delta, kappa), albeit with differing affinities. Peptides derived from proenkephalin and prodynorphin are broadly distributed in brain, and mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been utilized to explore the functions of the opioid peptides in specific behaviors and brain circuits. These methods include directly administering the peptides ex vivo (i.e. to excised tissue) or in vivo (in animals), using antagonists of specific opioid receptors to infer endogenous peptide activity, and using positron-emission tomography (PET) to detect a change in receptor availability, a sign of peptide release. While each of these approaches have weaknesses, certain observations have been consistent across modalities thereby adding to our current understanding of the function of endogenous opioids. We briefly review the history of identification of opioid peptides, highlight the major findings, address several myths that are widely accepted but not supported by recent data, and discuss unanswered questions and future directions for research. SIGNIFICANCE STATEMENT: Activation of the opioid receptors by opiates and synthetic drugs leads to central and peripheral biological effects including analgesia and respiratory depression, but these may not be the primary functions of the endogenous opioid peptides. Instead, the opioid peptides play complex and overlapping roles in a variety of systems, including reward pathways, and an important direction for research is the delineation of the role of individual peptides.
Learn More >Overdose from opioids causes nearly 50 000 deaths in the US each year. Adverse consequences from opioid use are particularly pronounced among low-income and publicly insured individuals. However, little is known about patterns of opioid prescribing among non-US-born individuals in the US.
Learn More >Cluster headache (CH) is clinically associated with considerable psychosocial burden. However, instruments to assess and characterize psychosocial factors in cluster headache more specifically are lacking. This study aimed to develop a self-report questionnaire, which assesses the broadest possible spectrum of psychosocial factors in cluster headache, the Cluster Headache Scales (CHS).
Learn More >Transient receptor potential ankyrin 1 (TRPA1) is well documented as an important molecule in pain hypersensitivity following inflammation and nerve injury and in many other cellular biological processes. Here, we show that TRPA1 is expressed not only by sensory neurons of the dorsal root ganglia (DRG) but also in their adjacent satellite glial cells (SGCs), as well as nonmyelinating Schwann cells. TRPA1 immunoreactivity is also detected in various cutaneous structures of sensory neuronal terminals, including small and large caliber cutaneous sensory fibers and endings. The SGC-expressed TRPA1 is functional. Like DRG neurons, dissociated SGCs exhibit a robust response to the TRPA1-selective agonist allyl isothiocyanate (AITC) by an increase of intracellular Ca concentration ([Ca]). These responses are abolished by the TRPA1 antagonist HC030031 and are absent in SGCs and neurons from global TRPA1 null mice. SGCs and neurons harvested from DRG proximal to painful tissue inflammation induced by plantar injection of complete Freund's adjuvant show greater AITC-evoked elevation of [Ca] and slower recovery compared to sham controls. Similar TRPA1 sensitization occurs in both SGCs and neurons during neuropathic pain induced by spared nerve injury. Together, these results show that functional TRPA1 is expressed by sensory ganglia SGCs, and TRPA1 function in SGCs is enhanced after both peripheral inflammation and nerve injury, and suggest that TRPA1 in SGCs may contribute to inflammatory and neuropathic pain.
Learn More >Pain is increasingly treated with opioids. Potential harms of opioid therapy disproportionally affect older patients. This study aims to provide information on trends, nature and duration of opioid prescribing to older adults, in primary care and to explore differences between older patients from different ages.
Learn More >The cytokine, interleukin-23 (IL-23), can be critical for the progression of inflammatory diseases, including arthritis, and is often associated with T lymphocyte biology. We previously showed that certain lymphocyte-independent, inflammatory arthritis and pain models have a similar requirement for tumour necrosis factor (TNF), granulocyte macrophage-colony stimulating factor (GM-CSF), and C-C motif ligand 17 (CCL17). Given this correlation in cytokine requirements, we explored whether IL-23 might interact with this cytokine cluster in the control of arthritic and inflammatory pain.
Learn More >Endogenous lipid mediators are proposed to contribute to headache and facial pain by activating trigeminal neurons (TN). We recently identified 11-hydroxy-epoxide- and 11-keto-epoxide derivatives of linoleic acid (LA) that are present in human skin and plasma and potentially contribute to nociception. Here we expand upon initial findings by examining the effects of 11-hydroxy- and 11-keto-epoxide-LA derivatives on TN activation in comparison to LA, the LA derivative [9-hydroxy-octadecadienoic acid (9-HODE)] and prostaglandin E (PGE). 11-hydroxy- and 11-keto-epoxide-LA derivatives elicited Ca transients in TN subpopulations. The proportion of neurons responding to test compounds (5 μM, 5 min) ranged from 16.2 ± 3.8 cells (11 K-9,10E-LA) to 34.1 ± 2.4 cells (11H-12,13E-LA). LA and 9-HODE (5 μM, 5 min) elicited responses in 11.6 ± 3.1% and 9.7 ± 3.4% of neurons, respectively. 11H-12,13E-LA, 11K-12,13E-LA, and 11H-9,10E-LA produced Ca responses in significantly higher proportions of neurons compared to either LA or 9-HODE (F (6, 36) = 5.12, P = 0.0007). 11H-12,13E-LA and 11H-9,10E-LA increased proportions of responsive neurons in a concentration-dependent fashion, similar to PGE. Most sensitive neurons responded to additional algesic agents (32.9% to capsaicin, 40.1% to PGE, 58.0% to AITC), however 20.6% did not respond to any other agent. In summary, 11-hydroxy-epoxide derivatives of LA increase trigeminal neuron excitability, suggesting a potential role in headache or facial pain.
Learn More >Disruption of blood-brain barrier integrity and dramatic failure of brain ion homeostasis including fluctuations of pH occurs during cortical spreading depression (CSD) events associated with several neurological disorders, including migraine with aura, traumatic brain injury and stroke. NHE1 is the primary regulator of pH in the central nervous system. The goal of the current study was to investigate the role of sodium-hydrogen exchanger type 1 (NHE1) in blood brain barrier (BBB) integrity during CSD events and the contributions of this antiporter on xenobiotic uptake. Using immortalized cell lines, pharmacologic inhibition and genetic knockdown of NHE1 mitigated the paracellular uptake of radiolabeled sucrose implicating functional NHE1 in BBB maintenance. In contrast, loss of functional NHE1 in endothelial cells facilitated uptake of the anti-migraine therapeutic, sumatriptan. In female rats, cortical KCl but not aCSF selectively reduced total expression of NHE1 in cortex and PAG but increased expression in trigeminal ganglia; no changes were seen in trigeminal nucleus caudalis. Thus, in vitro observations may have a significance in vivo to increase brain sumatriptan levels. Pharmacological inhibition of NHE1 prior to cortical manipulations enhanced the efficacy of sumatriptan at early time-points but induced facial sensitivity alone. Overall, our results suggest that dysregulation of NHE1 contributes to breaches in BBB integrity, drug penetrance, and the behavioral sensitivity to the antimigraine agent, sumatriptan.
Learn More >Delta opioid receptor (δ-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animal models. However, the role of agonist efficacy in generating different δ-receptor-mediated behaviors has not been thoroughly investigated. To this end, efficacy requirements for δ-receptor-mediated antihyperalgesia, antidepressant-like effects, and convulsions were evaluated by comparing the effects of the partial agonist BU48 and the full agonist SNC80 as well as changes in the potency of SNC80 following δ-receptor elimination. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. An antidepressant-like effect was evaluated in the forced swim test. Mice were observed for convulsions after treatment with SNC80 or the δ-opioid receptor partial agonist BU48. Ligand-induced G protein activation was measured by [35S]GTPγS binding in mouse forebrain tissue and δ-receptor number was measured by [3H]DPDPE saturation binding. BU48 produced antidepressant-like effects and convulsions but antagonized SNC80-induced antihyperalgesia. The potency of SNC80 was shifted to the right in δ-receptor heterozygous knockout mice and 5'-NTII treated mice, and the magnitude of potency shift differed across assays with the largest shift occurring in the thermal hyperalgesia assay followed by the forced swim test, and then convulsion observation. NTI antagonized these SNC80-induced behaviors with similar potencies suggesting that these effects are mediated by the same type of δ-receptor. These data suggest that δ-receptor-mediated behaviors display a rank order of efficacy requirement with antihyperalgesia having the highest requirement, followed by antidepressant-like effects and then convulsions. These findings further our understanding of the pharmacological mechanisms mediating the in vivo effects of δ-opioid receptor agonists. SIGNIFICANCE STATEMENT: Delta opioid receptor (δ-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animal models. This study evaluates pharmacological properties, specifically the role of agonist efficacy and receptor reserve, underlying these δ-receptor-mediated behaviors. These data suggest that δ-receptor-mediated behaviors display a rank order of efficacy requirement with antihyperalgesia having the highest requirement, followed by antidepressant-like effects and then convulsions.
Learn More >Biological sex influences inflammatory response, as there is a greater incidence of acute inflammation in men and chronic inflammation in women. Here, we report that acute inflammation is attenuated by X-inactive specific transcript (Xist), a female cell-specific nuclear long noncoding RNA crucial for X-chromosome inactivation. Lipopolysaccharide-mediated acute inflammation increased Xist levels in the cytoplasm of female mouse J774A.1 macrophages and human AML193 monocytes. In both cell types, cytoplasmic Xist colocalizes with the p65 subunit of NF-κB. This interaction was associated with reduced NF-κB nuclear migration, suggesting a novel mechanism to suppress acute inflammation. Further supporting this hypothesis, expression of 5' XIST in male cells significantly reduced IL-6 and NF-κB activity. Adoptive transfer of male splenocytes expressing Xist reduced acute paw swelling in male mice indicating that Xist can have a protective anti-inflammatory effect. These findings show that XIST has functions beyond X chromosome inactivation and suggest that XIST can contribute to sex-specific differences underlying inflammatory response by attenuating acute inflammation in women.
Learn More >In this study, we investigated the evolution of chronic pain in sickle cell patients (SCD) as an age-dependent phenomenon, and studied the frequency of vaso-occlusive episode frequency, opioid use, quantitative sensory testing (QST) and biomarkers of chronic pain (CP).
Learn More >Changes in serotonergic sensory modulation associated with overexpression of 5-HT receptors in the CNS have been implicated in the pathophysiology of neuropathic pain after peripheral nerve damage. 5-HT receptor antagonists such as ondansetron can potentially alleviate neuropathic pain, but have limited effectiveness, due potentially to limited CNS access. However, there is currently limited information on CNS disposition of systemically-administered 5-HT receptor antagonists. This study evaluated the cerebrospinal fluid (CSF) disposition of ondansetron, as a surrogate of CNS penetration.
Learn More >Virtual reality (VR) has been shown to reduce pain, however outcome parameters of previous studies have primarily been of a subjective nature and susceptible to bias. This study investigated the effect of VR on cortical processing of evoked potentials (EPs) and subjectively reported pain. Additionally, we explored whether subjects' demographic and personal characteristics modulated the effect of VR analgesia.
Learn More >Calcitonin gene-related peptide (CGRP) has recently been implicated in the pathogenesis of post-traumatic headache (PTH), which raises the prospect for therapeutic use of monoclonal antibodies targeting CGRP or its receptor. Therefore, we decided to assess the efficacy, tolerability, and safety of erenumab for prevention of persistent PTH attributed to mild traumatic brain injury.
Learn More >To investigate the relationship of emotion regulation strategies (i.e., emotional suppression and reappraisal) with pain catastrophizing, fear of pain, pain intensity, worry, and depression as function of age in samples of older and younger adults.
Learn More >Chronic low back pain (cLBP) is the leading cause of disability, with a significant societal cost. It disproportionately affects Non-Hispanic Blacks and individuals of lower socioeconomic status (SES). The biopsychosocial framework has been used to study and manage cLBP, yet disparities persist.
Learn More >Clinical trials have shown the safety and clinical superiority of erenumab compared to placebo in chronic migraine (CM). The aim of this analysis is to evaluate the effectiveness and tolerability of erenumab in a real-world setting in patients with refractory CM.
Learn More >The Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide.
Learn More >The aim of this study was to determine if headache profile can predict future disability in patients with TTH.
Learn More >Evidence indicates that over half of all people with HIV (PWH) will experience nonmalignant chronic pain throughout their lifetimes, with increasing prevalence as they age. Peripheral neuropathy resulting from the neurotoxic effects of HIV itself and the medications used to treat HIV were widely considered the primary cause of acute and chronic pain early on in the antiretroviral treatment era. However, recent studies suggest a predominance of non-neuropathic (e.g., musculoskeletal) pain in PWH with uncertain etiology. Chronic pain is often widespread in PWH, affecting multiple body locations. Additional research is needed to better understand contributors to chronic pain in PWH, which is likely to include biological (e.g., immune dysregulation), psychological (e.g., substance abuse) and social (e.g., stigma) factors.
Learn More >Visual snow manifests as a pan-field, dynamic visual disturbance described as continuous TV-static-like tiny flickering dots. Current diagnostic criteria further require at least two additional symptoms for the Visual Snow Syndrome (VSS) from: palinopsia (afterimages and trailing), entoptic phenomena (floaters, blue field entoptic phenomenon, photopsia, self-light of the eye), photophobia and nyctalopia. Our objective was to compare the phenotype of VSS in an Italian and British population.
Learn More >Opioids are widely used in clinical practice because of their strong analgesia. However, their use is restricted by such factors as tolerance and opioid-induced hyperalgesia (OIH), so it is critical to find ways to reduce the dosage of opioids to avoid the side effects. In this study, we demonstrated for the first time the regulatory role of A20 in morphine analgesia. By overexpressing and knocking down A20 in the spinal cord of mice, we found that A20 enhanced morphine analgesia rather than tolerance. Then, at the cellular level, different methods were used to confirm that A20 could not only strengthen the inhibition of cAMP induced by opioids drugs, but also affect μ opioid receptor (MOR) and ERK phosphorylation. In addition, we found that A20 interacted with MOR inhibitory protein β-arrestin2, which could be enhanced by MOR agonists. Furthermore, there was evidence that A20 could inhibit β-arrestin2 recruitment. Collectively, our results indicated that A20 in the spinal cord could enhance morphine analgesia and increase MOR function through β-arrestin2. Upregulating A20 expression may be a potential strategy to improve the therapeutic profile of opioids and reduce their side effects.
Learn More >Diabetic mechanical allodynia (DMA) is a common manifestation in patients with diabetes mellitus, and currently, no effective treatment is available. Transient receptor potential vanilloid 4 (TRPV4) is involved in mechanical hypersensitivity resulting from varying aetiologies in animal, but its expression pattern during DMA and whether it contributes to this condition are still unclear. We investigated the spatial and temporal expression patterns of TRPV4 in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) by qRT-PCR, Western blotting and immunofluorescence assays. The pathophysiological role of TRPV4 in DMA was also investigated by intrathecal application of the TRPV4 selective antagonist HC-067047 or the agonist GSK1016790A. The results showed that both the mRNA and protein levels of TRPV4 were strikingly upregulated on day 14 in the rats with DMA. The increase in TRPV4 was mainly observed in the soma and central processes of calcitonin gene-related peptide (CGRP)- or neurofilament 200 kDa (NF200)-containing DRG neurons. Both single and repetitive intrathecal applications of HC-067047 (400 ng/kg) significantly alleviated mechanical allodynia in the rats with DMA, whereas a single application of GSK1016790A (200 ng/kg) aggravated mechanical allodynia. The present data suggest that TRPV4 undergoes expression changes that are associated with mechanical hypersensitivity in diabetic rats. TRPV4 may be a new molecular target for developing a clinical strategy to treat this intractable neuropathic pain.
Learn More >The autoimmune disease rheumatoid arthritis (RA) affects approximately 1% of the global population. RA is characterized with chronic joint inflammation and often associated with chronic pain. The imbalance of pro-inflammatory and anti-inflammatory macrophages is a feature of RA progression. Glial cells affecting neuronal sensitivity at both peripheral and central levels may also be important for RA progression and associated pain. Genetic variants in the T cell death-associated gene 8 (TDAG8) locus are found to associate with spondyloarthritis. TDAG8 was also found involved in RA disease progression and associated hyperalgesia in the RA mouse model. However, its modulation in RA remains unclear.
Learn More >There is histological evidence of microstructural changes in the zygomaticotemporal branch of the trigeminal nerve in migraineurs. This raises the possibility that altered trigeminal nerve properties contribute to migraine pathophysiology. Whilst it is not possible to explore the anatomy of small trigeminal nerve branches it is possible to explore the anatomy of the trigeminal root entry zone using magnetic resonance imaging in humans. The aim of this investigation is to assess the microstructure of the trigeminal nerve in vivo to determine if nerve alterations occur in individuals with episodic migraine.
Learn More >Nicotinic acetylcholine receptors (nAChRs) have emerged as a novel therapeutic strategy for pain and inflammatory disorders. In particular, α4β2∗, α7, and α9α10 nAChR subtypes have been investigated as potential targets to treat pain. The nAChRs are distributed on the pain transmission pathways, including central and peripheral nervous systems and immune cells as well. Several agonists for α4β2∗ nAChR subtypes have been investigated in multiple animal pain models with promising results. However, studies in human indicated a narrow therapeutic window for α4β2∗ agonists. Furthermore, animal studies suggest that using agonists for α7 nAChR subtype and antagonists for α9α10 nAChR subtypes are potential novel therapies for chronic pain management, including inflammatory and neuropathic pain. More recently, alternative nAChRs ligands such as positive allosteric modulators and silent agonists have shown potential to develop into new treatments for chronic pain.
Learn More >Pain is the most common and troublesome complaint in rheumatoid arthritis (RA). This study aimed to assess the prevalence and clinical implications of unacceptable pain in an inception cohort of patients with RA.
Learn More >This meta-analytical review assesses the utility of the Trail Making Test (TMT), versions A and B, in detecting migraine-related cognitive deficits. A comprehensive literature search was performed in two electronic databases and other sources to obtain relevant studies administering TMT to migraine patients. Search terms included "migraine" and "Trail Making". Only studies in which the TMT-A, TMT-B or both were administered to adult patients suffering from migraine with and without aura were included. All pooled meta-analyses were based on random effects models. A total of 14 studies for TMT-A and 15 for TMT-B met inclusion criteria and were subjected to meta-analyses. Results showed that performance is worse in migraine patients than in controls for both the TMT-A (Hedges' g = -.28) and TMT-B (g = -.37), with no difference between migraine with and without aura. This study demonstrates the sensitivity of the TMT in detecting cognitive alterations in migraine. This test should be considered for inclusion in cognitive batteries assessing patients with migraine.
Learn More >Itch and pain are important attention-demanding sensations that allow adaptive responses to potential bodily harm. An attentional bias towards itch and pain stimuli, i.e. preferential attention allocation towards itch- and pain-related information, has been found in healthy, as well as patient groups. However, it remains unclear whether attentional bias for itch and pain differs from a general bias towards negative information. Therefore, this study investigated attentional bias towards itch and pain in 70 itch- and pain-free individuals. In an attention task, itch- and pain-related stimuli, as well as negative stimuli, were presented alongside neutral stimuli. The results did not indicate an attentional bias towards itch-, pain-, and negative visual information. This finding suggests that people without itch and pain symptoms do not prioritize itch- and pain-related information above neutral information. Future research should investigate whether attention towards itch- and pain-related information might be biased in patients with chronic itch and pain.
Learn More >Affordable virtual reality (VR) technology is now widely available. Billions of dollars are currently being invested into improving and mass producing VR and augmented reality products.
Learn More >Primary headaches are less common and differ in presentation in older versus younger individuals. Secondary headaches become more common among older patients.
Learn More >Electroencephalography During Nociceptive Stimulation in Chronic Pain Patients: A Systematic Review.
With its high temporal resolution, electroencephalography (EEG), a technique that records electrical activity of cortical neuronal cells, is a potentially suitable technique to investigate human somatosensory processing. By using EEG, the processing of (nociceptive) stimuli can be investigated, along with the functionality of the nociceptive pathway. Therefore, it can be applied in chronic pain patients to objectify whether changes have occurred in nociceptive processing. Typically, so-called event-related potential (ERP) recordings are used, where EEG signals are recorded in response to specific stimuli and characterized by latency and amplitude.
Learn More >The purpose of this review is to discuss the current evidence for acupuncture in migraine and to provide insight into which patients may benefit most from acupuncture.
Learn More >The purpose of this review is to summarize the role of avoidance behavior in headache-related disability and overview relevant clinical implications.
Learn More >Our aim was to investigate the relationship between coexisting cluster headache (CH) and migraine with anxiety and depression during active cluster bouts, and how symptoms change during remission.
Learn More >Non-bacterial prostatitis is an inflammatory disease that is difficult to treat. Oligonucleotide aptamers are well known for their stability and flexibility in conjugating various inflammatory molecules. In this study, we investigated the effects of inflammatory cytokine-targeting aptamers (ICTA), putative neutralizers of TNF-alpha and IL-1 beta activation, on local carrageenan-induced prostate inflammation, allodynia, and hyperalgesia in rats. In vitro evaluation confirmed the binding capability of ICTA. Intraprostatic injection of carrageenan or control vehicle was performed in six-week-old rats, and ICTA (150 µg) or vehicle was administered in the prostate along with carrageenan injection. The von Frey filament test was performed to determine mechanical allodynia, and prostate inflammation was examined seven days after drug administration. Local carrageenan administration resulted in a reduction of the tactile threshold. The levels of mononuclear cell infiltration, pro-inflammatory cytokine interleukin-1 beta (b), caspase-1 (casp-1), and Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing proteins 1 and 3 (NALP1 and NALP3) in the prostate of rats were increased seven days after carrageenan injection. Treatment with ICTA significantly attenuated the carrageenan-induced hyperalgesia and reduced the elevated levels of proteins including TNF-a and IL-1b in the rats. Apoptosis markers, B-cell lymphoma 2-associated X protein (Bax) and caspase-3, were elevated in ICTA-treated Chronic pelvic pain syndrome (CPPS) rats. These results suggest that ICTA provides protection against local carrageenan-induced enhanced pain sensitivity, and that the neutralization of proinflammatory cytokines may result in inflammatory cell apoptosis.
Learn More >Paclitaxel-induced peripheral neuropathy (PIPN) is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous system. Antihypertensive drug losartan, an angiotensin II receptor type 1 (AT1R) blocker, was shown to have anti-inflammatory and neuroprotective effects in disease models, predominantly via activation of peroxisome proliferator-activated receptor gamma (PPARγ). Here, the effect of systemic losartan treatment (100 mg/kg/d) on mechanical allodynia and neuroinflammation was evaluated in rat PIPN model. The expression of pro-inflammatory markers protein and mRNA levels in dorsal root ganglia (DRGs) and spinal cord dorsal horn (SCDH) were measured with Western blot, ELISA and qPCR 10 and 21 days after PIPN induction. Losartan treatment attenuated mechanical allodynia significantly. Paclitaxel induced overexpression of C-C motif chemokine ligand 2 (CCL2), tumour necrosis alpha (TNFα) and interleukin-6 (IL-6) in DRGs, where the presence of macrophages was demonstrated. Neuroinflammatory changes in DRGs were accompanied with glial activation and pro-nociceptive modulators production in SCDH. Losartan significantly attenuated paclitaxel-induced neuroinflammatory changes and induced expression of pro-resolving markers (Arginase 1 and IL-10) indicating a possible shift in macrophage polarization. Considering the safety profile of losartan, acting also as partial PPARγ agonist, it may be considered as a novel treatment strategy for PIPN patients.
Learn More >Treating persistent neuropathic pain remains a major clinical challenge. Current conventional treatment approaches carry a substantial risk of toxicity and provide only transient pain relief. In this work, we show that the activity and expression of the inflammatory mediator secretory phospholipase-A (sPLA) enzyme increases in the spinal cord after painful nerve root compression. We then develop phospholipid micelle-based nanoparticles that release their payload in response to sPLA activity. Using a rodent model of neuropathic pain, phospholipid micelles loaded with the sPLA inhibitor, thioetheramide-PC (TEA-PC), are administered either locally or intravenously at the time of painful injury or 1-2 days afterwards. Local micelle administration immediately after compression prevents pain for up to 7 days. Delayed intravenous administration of the micelles attenuates existing pain. These findings suggest that sPLA inhibitor-loaded micelles can be a promising anti-inflammatory nanotherapeutic for neuropathic pain treatment.
Learn More >This study examined the cross-sectional associations among pain intensity, pain catastrophizing, and sleep disturbance among patients receiving methadone maintenance treatment (MMT) for opioid use disorder (OUD) and reporting co-occurring chronic pain.
Learn More >Cluster headache is a severe primary headache with a similar prevalence to that of multiple sclerosis. Cluster headache is characterised by unilateral trigeminal distribution of pain, ipsilateral cranial autonomic features, and a tendency to circadian and circannual periodicity.
Learn More >In migraine or primary headache in children, parents play a fundamental role in pain management. For this narrative review, PubMed, Google Scholar, and Psych Info were searched using the terms "parent headache", "mother/father headache", "parental impact headache", "alexithymia parents headache", "catastrophizing parent headache", "family headache", "children parent headache", and "quality of life family headache". Articles were chosen for inclusion based on their relevance in to the topic.
Learn More >Chronic widespread pain (CWP) is a complex pain condition characterized by generalized musculoskeletal pain and often associated with other symptoms. An important clinical feature is widespread increased pain sensitivity such as lowered pain thresholds for mechanical stimuli (pressure pain thresholds [PPT]). There is a growing interest in investigating the activated neurobiological mechanisms in CWP, which includes fibromyalgia. In CWP, strong significant correlations have been found between muscle protein patterns and PPT. This explorative proteomic study investigates the multivariate correlation pattern between plasma proteins and PPT in CWP and in healthy controls (CON). In addition, this study analyses whether the important proteins for PPT differ between the 2 groups.Using 2-dimensional gel electrophoresis, we analyzed the plasma proteome of the CWP (n = 15) and the CON (n = 23) and proteins were identified using mass spectrometry. For both the CWP and the CON, the associations between the identified proteins and PPT were analyzed using orthogonal partial least square in 2 steps.Significant associations between certain plasma proteins and PPT existed both in CWP (R = 0.95; P = .006) and in CON (R = 0.89; P < .001). For both groups of subjects, we found several proteins involved in PPT that reflect different biological processes. The plasma proteins as well as the biological processes involved in PPT differed markedly between the 2 groups of subjects.This study suggests that plasma protein patterns are associated with pain thresholds in CWP. Using the plasma proteome profile of CWP to study potential biomarker candidates could provide a snapshot of ongoing systemic mechanisms in CWP.
Learn More >Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that 1) prevention and treatment of OIPN still remains an important and unmet clinical need, 2) further, high-quality research is mandatory in order to achieve reliable and effective results, and 3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN.
Learn More >Substance use disorders (SUDs) are frequently accompanied by affective symptoms that promote negative reinforcement mechanisms contributing to SUD maintenance or progression. Despite their widespread use as analgesics, chronic or excessive exposure to alcohol, opioids, and nicotine produces heightened nociceptive sensitivity, termed hyperalgesia. This review focuses on the contributions of neuropeptide (CRF, melanocortin, opioid peptide) and cytokine (IL-1β, TNF-α, chemokine) systems in the development and maintenance of substance-induced hyperalgesia. Few effective therapies exist for either chronic pain or SUD, and the common interaction of these disease states likely complicates their effective treatment. Here we highlight promising new discoveries as well as identify gaps in research that could lead to more effective and even simultaneous treatment of SUDs and co-morbid hyperalgesia symptoms.
Learn More >The effectiveness of Spinal Cord Stimulation (SCS) as pain-relieving treatment for Failed Back Surgery Syndrome (FBSS) has already been demonstrated. However, potential structural and functional brain alterations resulting from subsensory SCS are less clear. The aim of this study is to test structural volumetric changes in a priori chosen regions of interest related to chronic pain after 1 month and 3 months of high-frequency SCS, in patients with FBSS.
Learn More >Abdominal pain-predominant functional gastrointestinal disorders encompass a group of chronic conditions featuring abdominal pain where no serious gastrointestinal or intra-abdominal pathology is present. The Rome IV classification system defines and categorises this group based on symptomatology as: functional dyspepsia, irritable bowel syndrome, functional abdominal pain – not otherwise specified and abdominal migraine. These conditions can impact the functioning of the child and family significantly and are challenging to manage. Although the causes of these conditions are not clear, recent years have seen an improved understanding of underlying pathophysiology and identification of effective management options for these conditions.
Learn More >Background and aims A considerable research-literature focuses on pain during labor and associations with postpartum persistent pain and depression, with findings pointing in various directions. The aim of this study was to examine the role of labor pain and overall birth experience in the development of pain and depression 8 weeks after delivery. Methods The study sample was drawn from the Akershus Birth Cohort. Data from multiple sources were used, including the hospital's birth record (n = 4,391), questionnaire data from gestational week 17 of pregnancy (n = 3,752), 8 weeks postpartum (n = 2,217), and two questions about pain and birth experience asked within 48 h after delivery (n = 1,221). The Edinburgh Postnatal Depression Scale was used to measure postpartum depression, a single question was used to measure persistent pain 8 weeks postpartum, while pain and birth experience were measured by numeric rating scales. A history of pre-pregnant depression and chronic pain were measured through self-report questions in gestational week 17. A total of 645 women had complete data from all sources. We applied multiple imputation techniques to handle missing responses on the two questions about pain and birth experience. Results The results showed that neither labor pain nor birth experience were associated with persistent pain 8 weeks postpartum, whereas pain before pregnancy (OR 3.70; 95% CI 2.71-5.04) and a history of depression (OR 2.31; 95% CI 1.85-2.88) were statistically significant predictors of persistent pain. A negative birth experience was significantly (OR 1.16; 95% CI 1.04-1.29) associated with postpartum depression, whereas labor pain intensity was not. A history of depression (OR 3.95; 95% CI 2.92-5.34) and pre-pregnancy pain (OR 2.03; 95% CI 1.37-3.01) were important predictors of postpartum depression 8 weeks after delivery. Conclusions and implications Whilst the relationship between labor pain intensity and postpartum pain and depression remain unclear, our results do imply the need to screen for previous depression and chronic pain conditions in pregnant women, as well as consider preventive measures in those who screen positive.
Learn More >This systematic review appraises the evidence from human clinical trials comparing post-operative pain scores and opioid consumption in patients receiving intra-articular (IA) ketamine versus other modalities of analgesia after orthopedic joint procedures.
Learn More >Microglia are the resident immune cells in the CNS, which survey the brain parenchyma for pathogens, initiate inflammatory responses, secrete inflammatory mediators, and phagocyte debris. Besides, they play a role in the regulation of brain ion homeostasis and in pruning synaptic contacts and thereby modulating neural networks. More recent work shows that microglia are embedded in brain response related to stress phenomena, the development of major depressive disorders, and pain-associated neural processing. The microglia phenotype varies between activated-toxic-neuroinflammatory to non-activated-protective-tissue remodeling, depending on the challenges and regulatory signals. Increased inflammatory reactions result from brain damage, such as stroke, encephalitis, as well as chronic dysfunctions, including stress and pain. The dimension of damage/toxic stimuli defines the amplitude of inflammation, ranging from an on-off event to low but continuous simmering to uncontrollable. Pain, either acute or chronic, involves inflammasome activation at the point of origin, the different relay stations, and the sensory and processing cortical areas. This short review aimed at identifying a sinister role of the microglia-inflammasome platform for the development and perpetuation of acute and chronic central pain and its association with changes in CNS physiology.
Learn More >Mitochondrial respiratory chain dysfunction may be predisposing for the development of migraine, reflected in high migraine prevalence in patients with mitochondrial disease. Prevalence and impact of migraine in patients with proven mitochondrial disease and the current treatment efficacy were studied using online questionnaires. Patients were selected at the Internal Medicine Department. Headache was reported by 34 (55%) out of 62 patients. Migraine-criteria were met by 85% of them. Efficacy of migraine treatment was achieved in 4 patients. Given the high prevalence of migraine and current treatment insufficiency, migraine is a major threat of quality of life patients with mitochondrial disease.
Learn More >Although migraine is recognized as one of the most common and disabling diseases in the world, it is nonetheless still underestimated, underdiagnosed, and undertreated. The fact that migraine patients often tend to access the Web to search for headache-related information hinders patient-doctor relationships and one should also bear in mind that, unfortunately, text readability and medical literacy in the overall population may be the reason why patients' understanding of health information is compromised.
Learn More >Chronic pain and depression commonly occur together so dual-acting agents might be particularly useful. The population of patients with chemotherapy-induced neuropathy is increasing in parallel with the increase of population of cancer survivors and there is a compelling need for satisfactory treatment of symptoms of neuropathy and concomitant depression. We examined the effects of vortioxetine, a novel antidepressant with unique mechanism of action, on pain hypersensitivity and depression-like behavior in oxaliplatin-induced neuropathy model in mice (OIPN). Vortioxetine (1-10 mg/kg, p.o.) significantly and dose-dependently reduced mechanical allodynia in von Frey test and cold allodynia in acetone test in OIPN mice, in both repeated prophylactic and acute therapeutic treatment regimens. It also reduced depression-like behavior in the forced swimming test in OIPN mice, in both treatment paradigms. Its antiallodynic and antidepressive-like effects were comparable to those exerted by duloxetine (1-15 mg/kg, p.o.). The antiallodynic and antidepressive-like effects of repeatedly administered vortioxetine might be related to the increased content of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), detected in the brainstem of treated OIPN mice. These results indicate that vortioxetine could be potentially useful in prevention and treatment of chemotherapy-induced neuropathy, for the relief of pain and concomitant depressive symptoms. It should be further tested to this regard in clinical settings.
Learn More >To report the level and trends of prevalence, incidence and years lived with disability (YLDs) for osteoarthritis (OA) in 195 countries and territories from 1990 to 2017 by age, sex and Socio-demographic index (SDI; a composite of sociodemographic factors).
Learn More >Central post-stroke pain (CPSP) is chronic neuropathic pain due to a lesion or dysfunction of the central nervous system following cerebrovascular insult. This syndrome is characterized by chronic somatosensory abnormalities including spontaneous pain, hyperalgesia and allodynia, which localize to body areas corresponding to the injured brain region. However, despite its potential to impair activities of daily life and cause mood disorders after stroke, it is probably the least recognized complication of stroke. All currently approved treatments for CPSP have limited efficacy but troublesome side effects. The detailed mechanism underlying CPSP is still under investigation; however, its diverse clinical features indicate excessive central neuronal excitability, which is attributed to loss of inhibition and excessive neuroinflammation. Recently, exogenous epoxyeicosatrienoic acids (EETs) have been used to attenuate the mechanical allodynia in CPSP rats and proven to provide a quicker onset and superior pain relief compared to the current first line drug gabapentin. This anti-nociceptive effect is mediated by reserving the normal thalamic inhibition state through neurosteroid-GABA signaling. Moreover, mounting evidence has revealed that EETs exert anti-inflammatory effects by inhibiting the expression of vascular adhesion molecules, activating NFκB, inflammatory cytokines secretion and COX-2 gene induction. The present review focuses on the extensive evidence supporting the potential of EETs to be a multi-functional therapeutic approach for CPSP. Additionally, the role of EETs in the crosstalk between anti-CPSP and the comorbid mood disorder is reviewed herein.
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