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Loss of the sense of touch or numbness in fingertips and toes is one of the earliest sensory dysfunctions in patients receiving chemotherapy with anti-cancer drugs such as vincristine. However, mechanisms underlying this chemotherapy-induced sensory dysfunction is poorly understood. Whisker hair follicles are tactile organs in non-primate mammals which are functionally equivalent to human fingertips. Here we used mouse whisker hair follicles as a model system to explore how vincristine treatment induces the loss of the sense of touch. We show that chronic treatment of mice with vincristine impaired in vivo whisker tactile behavioral responses. In vitro electrophysiological recordings made from whisker hair follicle afferent nerves showed that mechanically evoked whisker afferent impulses were significantly reduced following vincristine treatment. Furthermore, patch-clamp recordings from Merkel cells of whisker hair follicles revealed a significant reduction of mechanically activated currents via Piezo2 channels in Merkel cells. Collectively, our results suggest that Piezo2 channel dysfunction in Merkel cells contribute to the loss of the sense of touch following the chemotherapy treatment regimen with vincristine.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse side effect of many anti-cancer chemotherapeutic treatments. CIPN often causes neuropathic pain in extremities, and oxidative stress has been shown to be a major contributing factor to this pain. In this study, we determined the site of oxidative stress associated with pain (specifically, mechanical hypersensitivity) in cisplatin- and paclitaxel-treated mouse models of CIPN and investigated the neurophysiological mechanisms accounting for the pain. C57BL/6N mice that received either cisplatin or paclitaxel (2 mg/kg, once daily on 4 alternate days) developed mechanical hypersensitivity to von Frey filament stimulations of their hindpaws. Cisplatin-induced mechanical hypersensitivity was inhibited by silencing of Transient Receptor Potential channels V1 (TRPV1)- or TRPA1-expressing afferents, whereas paclitaxel-induced mechanical hypersensitivity was attenuated by silencing of Afibers. While systemic delivery of phenyl N-tert-butylnitrone (PBN), a reactive oxygen species (ROS) scavenger, alleviated mechanical hypersensitivity in both cisplatin- and paclitaxel-treated mice, intraplantar PBN was effective only in cisplatin-treated mice, and intrathecal PBN, only in paclitaxel-treated mice. In a ROS-dependent manner, the mechanosensitivity of A/C fiber endings in the hindpaw skin was increased in cisplatin-treated mice, and the excitatory synaptic strength in the spinal dorsal horn was potentiated in paclitaxel-treated mice. Collectively, these results suggest that cisplatin-induced mechanical hypersensitivity is attributed to peripheral oxidative stress sensitizing mechanical nociceptors, whereas paclitaxel-induced mechanical hypersensitivity is due to central (spinal) oxidative stress maintaining central sensitization that abnormally produces pain in response to Afiber inputs.
Learn More >The nucleus accumbens (NAc) has been implicated in sleep, reward, and pain modulation, but the relationship between these functional roles is unclear. This study aimed to determine if NAc function at the onset and offset of a noxious thermal stimulus is enhanced by rewarding music, and if that effect is reversed by experimental sleep disruption. Twenty-one healthy subjects underwent functional MRI (fMRI) scans on two separate days following both uninterrupted sleep and experimental sleep disruption. During fMRI scans, participants experienced noxious stimulation while listening to individualized rewarding or neutral music. Behavioral results revealed that rewarding music significantly reduced pain intensity compared to neutral music and disrupted sleep was associated with decreased pain intensity in the context of listening to music. In whole-brain FWE cluster-corrected analysis, NAc was activated at pain onset, but not during tonic pain or at pain offset. Sleep disruption attenuated NAc activation at pain onset and during tonic pain. Rewarding music altered NAc connectivity with key nodes of the corticostriatal circuits during pain onset. Sleep disruption increased reward-related connectivity between the NAc and the anterior midcingulate cortex (aMCC) at pain onset. This study thus indicates that experimental sleep disruption modulates NAc function during the onset of pain in a manner that may be conditional on the presence of competing reward-related stimuli. These findings point to potential mechanisms for the interaction between sleep, reward, and pain, and suggest that sleep disruption affects both the detection and processing of aversive stimuli that may have important implications for chronic pain.
Learn More >Elevated excitability of primary afferent neurons underlies chronic pain in patients with functional or inflammatory bowel diseases. Recent studies have established an essential role for an enhanced transient receptor potential vanilloid subtype 1 (TRPV1) signaling in mediating peripheral hyperalgesia in inflammatory conditions. Since co-localization of Toll-like receptor 4 (TLR4) and TRPV1 has been observed in primary afferents including the trigeminal sensory neurons and the dorsal root ganglion (DRG) neurons, we test the hypothesis that TLR4 might regulate the expression and function of TRPV1 in primary afferent neurons in TNBS-induced colitis using the TLR4-deficient and the wild type (WT) C57 mice. Despite having a higher disease activity index following administration of TNBS, the TLR4 deficient mice showed less inflammatory infiltration in the colon than the WT mice. Increased expression of TLR4 and TRPV1 as well as increased density of capsaicin-induced TRPV1 current was observed in L4-S2 DRG neurons of WT colitis mice till two weeks post TNBS treatment. In comparison, TLR4 deficient colitis mice had lower TRPV1 expression and TRPV1 current density in DRG neurons with lower abdominal withdrawal response scores during noxious colonic distensions. In WT but not in TLR4-deficient DRG neurons, acute administration of the TLR4 agonist lipopolysacharide (LPS) increased the capsaicin-evoked TRPV1 current. In addition, we found that the canonical signaling downstream of TLR4 was activated in TNBS induced colitis in the WT but not in TLR4-deficient mice. These results indicate that TLR4 may play a major role in regulation of TRPV1 signaling and peripheral hyperalgesia in inflammatory conditions.
Learn More >Inhibitory pain modulation has been reported to be deficient in adults across different types of chronic pain, including migraine. To determine if a similar phenomenon occurs in youth, we performed a quantitative sensory testing investigation in adolescents with migraine (N=19). These patients were compared to healthy adolescents with (Fam-His; N=20) or without (Healthy; N=29) a family history of migraine (e.g., first degree relative with migraine). Subjects were first familiarized with the stimuli and visual analog rating scales using graded noxious stimuli (0°C, 43-49°C range). These data were used to explore potential pain sensitivity differences between the groups. Pain inhibition was assessed by conditioned pain modulation (CPM), which used both suprathreshold heat pain (heat CPM) and pressure pain thresholds (pressure CPM) as the test stimuli before and during cold water immersion (8°C). In response to the graded heat stimuli Fam-His participants reported higher pain intensity ratings compared to migraine patients, who in turn, reported higher pain intensity ratings than the healthy controls [F=3.6, (df=2, 459), p=0.027]. For heat- and pressure- CPM, there was no significant group difference in the magnitude of CPM responses. Thus, adolescents with migraine and healthy adolescents have similar inhibitory pain modulation capability despite having marked differences in pain sensitivity. Although Fam-His participants are asymptomatic, they demonstrate alterations in pain processing which may serve as markers for prediction of migraine development.
Learn More >Characterize the frequency, intensity, characteristics and associations of pain from AD.
Learn More >Despite enormous investment in research and development of novel treatments, there remains a lack of predictable, effective, and safe therapeutics for human chronic neuropathic pain (NP) afflictions. NP continues to increase among the population and treatments remain a major unmet public health care need. In recent years, numerous costly (time and money) failures have occurred attempting to translate successful animal pain model results, typically using rodents, to human clinical trials. These continued failures point to the essential need for better animal models of human pain conditions. To address this challenge, we have previously developed a peripheral neuritis trauma (PNT) model of chronic pain induced by a proximal sciatic nerve irritation in pigs, which have a body size, metabolism, skin structure, and cutaneous innervation more similar to humans. Here, we set out to determine the extent that the PNT model presents with cutaneous neuropathologies consistent with those associated with human chronic NP afflictions. Exactly as is performed in human skin biopsies, extensive quantitative multi-molecular immunofluorescence analyses of porcine skin biopsies were performed to assess cutaneous innervation and skin structure. ChemoMorphometric Analysis (CMA) results demonstrated a significant reduction in small caliber intraepidermal nerve fiber (IENF) innervation, altered dermal vascular innervation, and aberrant analgesic/algesic neurochemical properties among epidermal keratinocytes, which are implicated in modulating sensory innervation. These comprehensive pathologic changes very closely resemble those observed from CMA of human skin biopsies collected from NP afflictions. The results indicate that the porcine PNT model is more appropriate for translational NP research compared with commonly utilized rodent models. Because the PNT model creates cutaneous innervation and keratinocyte immunolabeling alterations consistent with human NP conditions, use of this animal model for NP testing and treatment response characteristics will likely provide more realistic results to direct successful translation to humans.
Learn More >Surgical care episodes place opioid-naive patients at risk for transitioning to new persistent postoperative opioid use. With one of the central principles being the application of multimodal pain interventions to reduce the reliance on opioid-based medications, enhanced recovery pathways provide a framework that decreases perioperative opioid use. The fourth Perioperative Quality Initiative brought together a group of international experts representing anesthesiology, surgery, and nursing with the objective of providing consensus recommendations on this important topic. Fourth Perioperative Quality Initiative was a consensus-building conference designed around a modified Delphi process in which the group alternately convened for plenary discussion sessions in between small group discussions. The process included several iterative steps including a literature review of the topics, building consensus around the important questions related to the topic, and sequential steps of content building and refinement until agreement was achieved and a consensus document was produced. During the fourth Perioperative Quality Initiative conference and thereafter as a writing group, reference applicability to the topic was discussed in any area where there was disagreement. For this manuscript, the questions answered included (1) What are the potential strategies for preventing persistent postoperative opioid use? (2) Is opioid-free anesthesia and analgesia feasible and appropriate for routine operations? and (3) Is opioid-free (intraoperative) anesthesia associated with equivalent or superior outcomes compared to an opioid minimization in the perioperative period? We will discuss the relevant literature for each questions, emphasize what we do not know, and prioritize the areas for future research.
Learn More >We examined the effect of immobilization, low-intensity muscle contraction exercise, and transcutaneous electrical nerve stimulation (TENS) on tissue inflammation and acute pain following the onset of arthritis in a rat model. Sixty Wistar rats were divided into five groups: (1) Arthritis group, (2) arthritis and immobilization (Immobilization group), (3) arthritis and low intensity muscle contraction (Exercise group), (4) arthritis and TENS (TENS group), and (5) sham arthritis (Sham group). Arthritis was induced in the right knee joints by single injection of 3% kaolin and carrageenan. Immobilization of the right hindlimb was conducted by full extension of the right knee joints and full plantar flexion of the ankle joints using a plaster cast for 7 days after injection. The right quadriceps muscles were subjected to electrical stimulation (frequency: 50 Hz; intensity: 2-3 mA) for 20 min/day as contraction exercise for one week. TENS was delivered at 20 min/day for one week (frequency: 50 Hz; intensity: 1 mA). The pressure pain threshold (PPT) and paw withdrawal response (PWR) were evaluated at 1 and 7 days after injection. We also analyzed the number of CD68-positive cells in the synovium by immunohistochemistry and determined the expression level of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn with immunofluorescence. Improvements of both PPT and PWR were observed in the Exercise group at 7 days after injection compared to those of the Arthritis and Immobilization groups, although only improvement of PPT was observed in the TENS group. The number of CD68-positive cells in the synovium and CGRP expression in the dorsal horn decreased only in the Exercise group. These results suggested that low-intensity muscle contraction exercise might be a better treatment for reduction of arthritis-induced inflammation and acute pain compared to immobilization and TENS.
Learn More >This is the first update of a review published in 2015, Issue 1. Chronic pain is common during childhood and adolescence and is associated with negative outcomes, such as increased severity of pain, reduced function, and low mood. Psychological therapies, traditionally delivered face-to-face with a therapist, are efficacious at reducing pain intensity and disability. To address barriers to treatment access, such as distance and cost of treatment, technology is being used to deliver these psychological therapies remotely. Therapies delivered remotely, such as via the Internet, computer-based programmes, and smartphone applications, can be used to deliver treatment to children and adolescents with chronic pain.
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