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Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxidative stress, and alterations of transcriptional programs in both the peripheral and central nervous systems. Moreover, we describe the necessity of advancing studies that identify the potential efficacy of approved drugs on the basis of pathological mechanisms, as this is a convincing strategy for rapid translation to patients with cancer and BIPN.
Learn More >P2X7 receptors are responsible for triggering inflammatory responses contributing to processes of pain in articular tissues. This study aimed to investigate whether the activation of the P2X7 receptor located in the temporomandibular joint (TMJ) tissues induces nociception through an inflammatory mechanisms and/or the activation of C-fibers (small-diameter primary afferents) of rats' TMJ.
Learn More >The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.
Learn More >The genetic background of pain is becoming increasingly well understood, which opens up possibilities for predicting the individual risk of persistent pain and the use of tailored therapies adapted to the variant pattern of the patient's pain-relevant genes. The individual variant pattern of pain-relevant genes is accessible via next-generation sequencing, although the analysis of all "pain genes" would be expensive. Here, we report on the development of a cost-effective next generation sequencing-based pain-genotyping assay comprising the development of a customized AmpliSeq™ panel and bioinformatics approaches that condensate the genetic information of pain by identifying the most representative genes. The panel includes 29 key genes that have been shown to cover 70% of the biological functions exerted by a list of 540 so-called "pain genes" derived from transgenic mice experiments. These were supplemented by 43 additional genes that had been independently proposed as relevant for persistent pain. The functional genomics covered by the resulting 72 genes is particularly represented by mitogen-activated protein kinase of extracellular signal-regulated kinase and cytokine production and secretion. The present genotyping assay was established in 61 subjects of Caucasian ethnicity and investigates the functional role of the selected genes in the context of the known genetic architecture of pain without seeking functional associations for pain. The assay identified a total of 691 genetic variants, of which many have reports for a clinical relevance for pain or in another context. The assay is applicable for small to large-scale experimental setups at contemporary genotyping costs.
Learn More >Virtual reality (VR) has been shown to produce analgesic effects during different experimental and clinical pain states. Despite this, the top-down mechanisms are still poorly understood. In this study, we examined the influence of both a real and sham (i.e. the same images in 2D) immersive arctic VR environment on conditioned pain modulation (CPM) and in a human surrogate model of central sensitisation in 38 healthy volunteers. CPM and acute heat pain thresholds (HPT) were assessed before and during VR/sham exposure in the absence of any sensitisation. In a follow-on study, we used the cutaneous high frequency stimulation (HFS) model of central sensitisation and measured changes in mechanical pain sensitivity (MPS) in an area of heterotopic sensitisation before and during VR/sham exposure. There was an increase in CPM efficiency during the VR condition compared to baseline (P<0.01). In the sham condition, there was a decrease in CPM efficiency compared to baseline (P<0.01) and the real VR condition (P<0.001). Neither real nor sham VR had any effect on pain ratings reported during the conditioning period or on HPT. There was also an attenuation of MPS during the VR condition indicating a lower sensitivity compared to sham (P<0.05). We conclude that exposure to an immersive VR environment has no effect over acute pain thresholds but can modulate dynamic CPM responses and mechanical hypersensitivity in healthy volunteers. Perspective: This study has demonstrated that exposure to an immersive virtual reality environment can modulate perceptual correlates of endogenous pain modulation and secondary hyperalgesia in a human surrogate pain model. These results suggest that virtual reality could provide a novel mechanism-driven analgesic strategy in patients with altered central pain processing.
Learn More >C tactile (CT) fibres, responsible for the so-called "affective" touch (AT), have drawn a fair amount of attention within the scientific community for their marked social dimension. However, while the pain-relieving potential of discriminative touch (DT) has been documented, proofs of the analgesic properties of AT are still scarce. Additionally, no study has so far tested its possible pain-relieving effect on a clinically-relevant model. Temporal summation of second pain (TSSP), otherwise referred to as 'wind-up', relies on repetitive stimulation of C-nociceptors and it is thought to reflect central sensitization, a process linked to many chronic pain conditions. In the present experimental, within participants, design we induced TSSP trough trains of ascending and descending repetitive heat stimulation. Forty-two healthy participants' pain was measured during two different tactile stimulations (stroking velocities AT: 10 cm/s; DT: 0.3 cm/s) or without concomitant tactile input. Since measures of pleasantness of the tactile stimulation have been found to strongly correlate with C-tactile fibres' firing rate, these, together with participants' body awareness, were also taken into account. Our results show that AT brought about a decrease of our participants' pain as opposed to both DT and no touch, while DT did not produce any significant pain reduction. Thus, only AT successfully modulated wind-up. As expected, AT was perceived more pleasant than DT, while a clear relationship between body awareness and pain was found only during DT. Targeting CT fibres could pave the way to new treatments for chronic pain conditions whose aetiology depend on abnormal C-nociceptors' physiology.
Learn More >A Systematic Review and Meta-Analysis of the Association between Perceived Injustice and Depression.
Perceived injustice is increasingly recognised as a risk factor for problematic recovery, with a growing body of evidence documenting its association with heightened pain, disability, medication use, anger and post-traumatic stress. The aim of this paper was to systematically review and critically appraise the association between perceived injustice and depressive symptomatology across a wide range of medical and mental health populations, including acute and chronic pain samples. A search of published, English language studies in the PubMed, EMBASE, CINAHL and PsycINFO databases from 1990 to June 2020 was performed. Thirty-three studies met inclusion criteria with a total sample of 5,425 individuals (61% female), primarily with acute injury or chronic pain. Results indicated a moderate to strong positive association between perceived injustice and depressive symptomatology (meta-analysis pooled effect of r = .57, 95% CI [0.55, 0.58], p < .001). A narrative synthesis of regression models indicated standardised beta coefficients between .19 and .66, with perceived injustice consistently contributing significant unique variance to the prediction of depression in final regression equations. Selection bias and response bias were common limitations in the studies. The clinical implications of an association between injustice and depression in acute and chronic pain are discussed. PROSPERO: CRD42019143465 PERSPECTIVE: This review demonstrates that in acute injury and chronic pain samples, perceived injustice is associated with depression. These findings could help clinicians in the field of pain and rehabilitation identify who may be at greater risk for a problematic recovery trajectory.
Learn More >Opioid usage for pain therapy is limited by its undesirable clinical effects, including paradoxical hyperalgesia, also known as opioid-induced hyperalgesia, (OIH). However, the mechanisms associated with the development and maintenance of OIH remain unclear. Here, we investigated the effect of serotonin inhibition by the 5-HT receptor antagonist, ondansetron (OND), as well as serotonin deprivation via its synthesis inhibitor para-chlorophenylalanine (PCPA), on mouse OIH models, with particular focus on astrocyte activation. Co-administering of OND and morphine, in combination with serotonin depletion, inhibited mechanical hyperalgesia and astrocyte activation in the spinal dorsal horn of mouse OIH models. Although previous studies have suggested that activation of astrocytes in the spinal dorsal horn is essential for the development and maintenance of OIH, herein, treatment with carbenoxolone (CBX), a gap junction inhibitor that suppresses astrocyte activation, did not ameliorate mechanical hyperalgesia in mouse OIH models. These results indicate that serotonin in the spinal dorsal horn, and activation of the 5-HT receptor play essential roles in OIH induced by chronic morphine, while astrocyte activation in the spinal dorsal horn serves as a secondary effect of OIH. Our findings further suggest that serotonergic regulation in the spinal dorsal horn may be a therapeutic target of OIH. PERSPECTIVE: The current study revealed that the descending serotonergic pain-facilitatory system in the spinal dorsal horn is crucial in OIH, and that activation of astrocytes is a secondary phenotype of OIH. Our study offers new therapeutic targets for OIH and may help reduce inappropriate opioid use.
Learn More >The present study investigated pain trajectories of husbands and wives over their mid-later years, the grouping of these trajectories, and differences in baseline biopsychosocial profiles and health and well-being outcomes in later years across the pain trajectory groups.
Learn More >The current study used data from a clinical trial to identify variables that are associated with and/or mediate the beneficial effects of four psychological chronic pain treatments: one teaching patients self-hypnosis to reduce pain intensity (HYP), one teaching self-hypnosis to change thoughts about pain (hypnotic cognitive therapy, or HYP-CT), one teaching cognitive restructuring skills to change thoughts about pain (cognitive therapy, or CT), and one providing education about pain (ED; included as an active control condition). Of 17 possible mechanism variables examined, and with alpha not corrected for multiple comparisons, significant between-group differences were observed for three. Two of these (changes in beliefs about control over pain and number of days of skill practice) were supported as mediators of the beneficial effects of HYP, CT, or HYP-CT, relative to ED. Six mechanism variables evidenced significant pre- to post-treatment changes in the sample as a whole, without showing significant between-group differences. Pre- to post-treatment changes in all six were associated with improvements in pain interference, pain intensity, or both. In addition, participant ratings of therapeutic alliance at post-treatment were associated significantly with improvements in both pain intensity and pain interference in the sample as a whole. Thus, of the 17 possible mediators examined, there were relatively few that serve as mediators for the beneficial effects of specific treatments; a larger number of variables predicted treatment outcome overall. The extent to which these variables are treatment mediators (i.e., are responsible for, rather than merely associated with, treatment-related improvements) will require further research.
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