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Abdominal pain continues to be a major challenge and unmet need in clinical practice. Normalization of bidirectional gut-brain signaling has generated much interest as a therapeutic approach to treat chronic abdominal pain. Vagal nerve stimulation (VNS) is emerging as a potential non-pharmacologic strategy for the treatment of abdominal pain. In this review paper, we will summarize the etiologies of chronic pain in gastrointestinal disorders and discuss the rational for VNS as a therapeutic approach to chronic abdominal pain, with particular emphasis in the gammaCore stimulator which allows for noninvasive VNS.
Learn More >Objectives Musculoskeletal (MSK) pain is a common complaint in patients with inflammatory bowel diseases (IBD). MSK pain in IBD has previously demonstrated association with symptoms of central sensitization; however it is uncertain whether these symptoms are influenced simply by the presence of MSK pain and/or IBD. Primary aim of this study was to investigate whether symptoms of central sensitization differed across three groups: IBD patients with and without MSK pain and healthy controls. Secondary aim was to investigate between-group differences for measures of somatosensory functioning. Methods Cross-sectional study was performed on adults with IBD. Assessments included: central sensitization inventory (CSI), pressure pain threshold, temporal summation, conditioned pain modulation, perceived stress, affect style, anxiety, depression, and pain catastrophizing. One-way analyses of variance and covariance were used to investigate between-group differences for measures of central sensitization and potential confounding by psychological factors. Results Study participants (n=66) were age/gender matched across three study groups. Between-group differences were solely demonstrated for CSI scores [F(2,63)=19.835, p<0.001, r=0.62], with IBD patients with MSK pain demonstrating the highest CSI scores and healthy controls the lowest. After controlling for individual psychological features, post hoc comparisons indicated that CSI scores were significantly different between-groups (p≤0.025) after controlling for most psychological variables, with the exception of perceived stress (p=0.063) and pain catastrophizing (p=0.593). Conclusions IBD patients as a whole demonstrated significantly greater symptoms of central sensitization compared to healthy controls. However, IBD patients with persistent MSK pain demonstrated the greatest symptoms of central sensitization compared to patients without MSK pain and healthy controls. Between-group differences for CSI in IBD patients with MSK were not confounded by psychological features. Implications Study results indicate that persistent MSK pain in IBD represents patients with greater central sensitization symptomology. This increased symptomology is suggestive of underlying mechanisms related to central sensitization, highlighting patient potentially at risk for worse pain experiences.
Learn More >The present study investigated the impact of advanced age on morphine modulation of persistent inflammatory pain in male and female rats. The impact of age, sex, and pain on μ-opioid receptor (MOR) expression and binding in the ventrolateral periaqueductal gray (vlPAG) was also examined using immunohistochemistry and receptor autoradiography. Intraplantar administration of complete Freund's adjuvant induced comparable levels of edema and hyperalgesia in adult (2-3 mos) and aged (16-18 mos) male and female rats. Morphine potency was highest in adult males, with a greater than two-fold increase in morphine EC observed in adult versus aged males (3.83 mg/kg vs. 10.16 mg/kg). Adult and aged female rats also exhibited significantly higher EC values (7.76 mg/kg and 8.74 mg/kg, respectively) than adult males. The upward shift in EC from adult to aged males was paralleled by a reduction in vlPAG MOR expression and binding. The observed age-related reductions in morphine potency and vlPAG MOR expression and binding have significant implications in pain management in the aged population.
Learn More >A recent study found that merely possessing a placebo analgesic reduces pain. The current study tested for a possible moderator of this effect. Specifically, does the mere possession of a placebo analgesic affect pain for individuals with and without immediate prior experience with the pain task? Healthy participants (N=127) were randomized to prior pain (PP) condition or without prior pain (No-PP) condition. In the PP condition, participants first did a preliminary trial of a cold pressor test (CPT) to induce direct experience with this pain stimulus. Then they were randomized to possess an inert cream described as either an analgesic cream or an anti-itch cream (pain-irrelevant control object). Participants then completed the main CPT. In the No-PP condition, participants underwent identical procedures and randomization except that they did not do a preliminary CPT, thus having no immediate prior CPT pain experience. We found a significant prior pain experience and possession status interaction effect on placebo analgesia. Participants in the No-PP condition showed evidence of lower pain when they merely possessed an analgesic cream than an anti-itch cream. Such mere possession effect was not found in the PP condition. The impact of expectancy and emotion on the underlying process are discussed. PERSPECTIVE: This article presents a novel finding that prior pain exposure and mere possession of a placebo analgesic predicted placebo analgesia. It offers a novel perspective on the time course of placebo effect. It provides practical implications on potential pain intervention for clinicians and paradigm design for researchers of placebo study.
Learn More >More than a quarter of veterans of the 1990-1991 Persian Gulf War suffer from Gulf War Illness (GWI), a chronic, multi-symptom illness that commonly includes musculoskeletal pain. Exposure to a range of toxic chemicals, including sarin nerve agent, are a suspected root cause of GWI. Moreover, such chemical exposures induce a neuroinflammatory response in rodents, which has been linked to several GWI symptoms in rodents and veterans with GWI. To date, a neuroinflammatory basis for pain associated with GWI has not been investigated. Here, we evaluated development of nociceptive hypersensitivity in a model of GWI. Male Sprague Dawley rats were treated with corticosterone in the drinking water for 7 days, to mimic high physiological stress, followed by a single injection of the sarin nerve agent surrogate, diisopropyl fluorophosphate. These exposures alone were insufficient to induce allodynia. However, an additional sub-threshold challenge (a single intramuscular injection of pH 4 saline) induced long-lasting, bilateral allodynia. Such allodynia was associated with elevation of markers for activated microglia/macrophages (CD11b) and astrocytes/satellite glia (GFAP) in the lumbar dorsal spinal cord and dorsal root ganglia (DRG). Additionally, Toll-like receptor 4 (TLR4) mRNA was elevated in the lumbar dorsal spinal cord, while IL-1β and IL-6 were elevated in the lumbar dorsal spinal cord, DRG, and gastrocnemius muscle. Demonstrating a casual role for such neuroinflammatory signaling, allodynia was reversed by treatment with either minocycline, the TLR4 inhibitor (+)-naltrexone, or IL-10 plasmid DNA. Together, these results point to a role for neuroinflammation in male rats in the model of musculoskeletal pain related to GWI. Therapies that alleviate persistent immune dysregulation may be a strategy to treat pain and other symptoms of GWI.
Learn More >Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10 mg/kg, i.p.), once every 2 days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the α6 subunit-containing GABA receptors (α6GABARs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG α6GABAR expression in NTG-treated mice, we demonstrated that an α6GABAR-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing α6GABAR modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered α6GABARs in TG are potential targets for migraine treatment. Thus, α6GABAR-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies.
Learn More >The effective and safe treatment of pain is an unmet health-care need. Current medications used for pain management are often only partially effective, carry dose-limiting adverse effects and are potentially addictive, highlighting the need for improved therapeutic agents. Most common pain conditions originate in the periphery, where dorsal root ganglion and trigeminal ganglion neurons feed pain information into the CNS. Voltage-gated sodium (Na) channels drive neuronal excitability and three subtypes – Na1.7, Na1.8 and Na1.9 – are preferentially expressed in the peripheral nervous system, suggesting that their inhibition might treat pain while avoiding central and cardiac adverse effects. Genetic and functional studies of human pain disorders have identified Na1.7, Na1.8 and Na1.9 as mediators of pain and validated them as targets for pain treatment. Consequently, multiple Na1.7-specific and Na1.8-specific blockers have undergone clinical trials, with others in preclinical development, and the targeting of Na1.9, although hampered by technical constraints, might also be moving ahead. In this Review, we summarize the clinical and preclinical literature describing compounds that target peripheral Na channels and discuss the challenges and future prospects for the field. Although the potential of peripheral Na channel inhibition for the treatment of pain has yet to be realized, this remains a promising strategy to achieve non-addictive analgesia for multiple pain conditions.
Learn More >Itch is defined as an unpleasant sensation that provokes a desire to scratch. Our understanding of neuronal circuits for itch information transmission and processing in the spinal dorsal horn (SDH) has progressively advanced following the identification of SDH neuron subsets that are crucial for scratching behavior in models of itch. However, little is known about the control of acute and chronic itch by descending signals from the brain to the SDH. In this study, using genetic approaches that enable cell-type and circuit-specific functional manipulation, we reveal an intrinsic potential of locus coeruleus (LC)-noradrenergic (NAergic) neurons that project to the SDH to control acute and chronic itch. Activation and silencing of SDH-projecting LC-NAergic neurons reduced and enhanced scratching behavior, respectively, in models of histamine-dependent and -independent acute itch. Furthermore, in a model of chronic itch associated with contact dermatitis, repetitive scratching behavior was suppressed by the activation of the descending LC-NAergic pathway and by knocking out NA transporters specific to descending LC-NAergic neurons using a CRISPR-Cas9 system. Moreover, patch-clamp recording using spinal slices showed that noradrenaline facilitated inhibitory synaptic inputs onto gastrin-releasing peptide receptor-expressing SDH neurons, a neuronal subset known to be essential for itch transmission. Our findings suggest that descending LC-NAergic signaling intrinsically controls acute and chronic itch and provide potential therapeutic strategies for the treatment of acute and chronic itch.
Learn More >Intravascular Endothelin-1 does not trigger or increase susceptibility to Spreading Depolarizations.
Spreading depolarizations (SD) likely manifest as aura in migraineurs. Triggers are unknown although vascular events have been implicated. Direct carotid puncture has been reported to trigger migraine with aura. The potent vasoconstrictor endothelin-1 (ET-1), which can be released from the endothelium under pathological conditions, may play a role. Here, we tested whether intracarotid ET-1 infusion triggers SD and whether systemic ET-1 infusion increases the susceptibility to SD.
Learn More >Prurigo nodularis (PN) is a chronic, pruritic, debilitating disease. Previous studies found that chronic pruritus in general negatively affects patients' quality of life (QoL). However, results about the impact of PN on QoL are conflicting. Our objective was to assess the QoL burden of PN. A systematic review was conducted of all published studies that assessed QoL measures in PN. OVID MEDLINE, EMBASE, SCOPUS, and Web of Science were searched. Pooled meta-analysis (means) was performed using random-effects weighting. Overall, 13 studies met inclusion criteria. All studies identified QoL reductions in patients suffering from PN compared to control groups. The most common QoL instrument used was the Dermatology Life Quality Index [n = 9 studies; pooled mean (95% confidence interval): 13.8 (10.6-16.9), denoting a very large effect]. In particular, PN was associated with substantial impact on multiple domains of QoL. No publication bias was detected. In conclusion, QoL is negatively impacted in PN. Future studies are necessary to determine the best instruments of measuring QoL in PN patients, better understand this association, and assess the impact in males and females separately. PROSPERO CRD42019136193.
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