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The basal ganglia modulate somatosensory pain pathways but it is unclear whether a common circuit exists to mitigate hyperalgesia in pain states induced by peripheral nociceptive stimuli. As a key output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr) may be a candidate for this role. To test this possibility, we optogenetically modulated SNr GABAergic neurons and examined pain thresholds in freely behaving male mice in inflammatory and neuropathic pain states as well as comorbid depression in chronic pain. We observed that stimulation of either SNr GABAergic neurons or their projections to the subthalamic nucleus (STN) significantly alleviated nociceptive responses in all pain states on the contralateral side and comorbid depression in chronic pain, and that this analgesic effect was eliminated when SNr-STN GABAergic projection was blocked. However, SNr modulation did not affect baseline pain thresholds. We also found that SNr-STN GABAergic projection was attenuated in pain states, resulting in disinhibition of STN neurons. Thus, impairment of the SNr-STN GABAergic circuit may be a common pathophysiology for the maintenance of hyperalgesia in both inflammatory and neuropathic pain states and the comorbid depression in chronic pain; compensating this circuit has potential to effectively treat related pain conditions.
Learn More >Somatosensory afferents are traditionally classified by soma size, myelination, and their response specificity to external and internal stimuli. Here, we propose the functional subdivision of the nociceptive somatosensory system into two branches. The exteroceptive branch detects external threats and drives reflexive-defensive reactions to prevent or limit injury. The interoceptive branch senses the disruption of body integrity, produces tonic pain with strong aversive emotional components, and drives self-caring responses toward to the injured region to reduce suffering. The central thesis behind this functional subdivision comes from a reflection on the dilemma faced by the pain research field, namely, the use of reflexive-defensive behaviors as surrogate assays for interoceptive tonic pain. The interpretation of these assays is now being challenged by the discovery of distinct but interwoven circuits that drive exteroceptive versus interoceptive types of behaviors, with the conflation of these two components contributing partially to the poor translation of therapies from preclinical studies.
Learn More >Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) – rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans we used simultaneous whole brain-spinal cord pharmacological-fMRI (N=39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.
Learn More >Rheumatic diseases are often associated to debilitating chronic pain, which remains difficult to treat and requires new therapeutic strategies. We had previously identified lysophosphatidyl-choline (LPC) in the synovial fluids from few patients, and shown its effect as a positive modulator of Acid-Sensing Ion Channel 3 (ASIC3) able to induce acute cutaneous pain in rodents. However, the possible involvement of LPC in chronic joint pain remained completely unknown. Here we show, from two independent cohorts of patients with painful rheumatic diseases, that the synovial fluid levels of LPC are significantly elevated, especially the LPC16:0 species, compared to post mortem controls. Moreover, LPC16:0 levels are correlated with pain outcomes in a cohort of osteoarthritis (OA) patients. However, LPC16:0 but do not appear to be the hallmark of a particular joint disease, since similar levels are found in the synovial fluids of a second cohort of patients with various rheumatic diseases. The mechanism of action was next explored by developing a pathology-derived rodent model. Intra-articular injections of LPC16:0 is a triggering factor of chronic joint pain in both male and female mice, ultimately leading to persistent pain and anxiety-like behaviors. All these effects are dependent on ASIC3 channels, which drive sufficient peripheral inputs to generate spinal sensitization processes. This study brings evidences from mouse and human supporting a role for LPC16:0 via ASIC3 channels in chronic pain arising from joints, with potential implications for pain management in OA and possibly across other rheumatic diseases.
Learn More >Stigmatizing language in the electronic health record (EHR) may alter treatment plans, transmit biases between clinicians, and alienate patients. However, neither the frequency of stigmatizing language in hospital notes, nor whether clinicians disproportionately use it in describing patients in particular demographic subgroups are known.
Learn More >Non-invasive vagus nerve stimulation (nVNS) is effective in several types of headache disorders. We sought to unravel the mechanism of how nVNS exhibits this efficacy. This study used a randomized, single-blind, sham-controlled, crossover-design, and comprised three projects with three independent cohorts of healthy participants. Project I (n=15) was explorative. Six quantitative sensory test (QST) parameters, including mechanical pain threshold (MPT), were measured over the left V1 dermatome and forearm, and compared before and after unilateral nVNS. Projects II (n=20) and III (n=21) were online pre-registered . QST parameters were compared over the left (Project II) or bilateral V1 and V3 dermatomes (Project III), respectively, in addition to the left forearm as a control. A secondary analysis of heart rate variability (HRV) using a historical control group was used to control for systemic effects of nVNS. Verum-nVNS induced trigeminal-specific modulation of pain threshold (i.e., MPT) over the left V1 in Project I, left V1 and V3 in Project II, and bilateral V1 and V3 in Project III. Data pooled from Project II and III demonstrated greater increase of MPT in the V1 vs. V3 dermatome. There were no differences associated with sham-nVNS in any projects. HRV parameters did not change after nVNS. Our results provide functional evidence of a long hypothesized functional trigemino-vagal system in humans and may explain why nVNS is effective in some headache but not in somatic pain disorders. Since unilateral nVNS modulated the trigeminal thresholds bilaterally, this effect is probably indirect through a central top-down mechanism.
Learn More >Recent sham-controlled studies suggest placebo effects contribute to acute pain relief following mindfulness interventions. However, the specific effects of mindfulness processes and their interaction with placebo effects remain unclear. This study aimed to characterize the role of mindfulness and placebo processes underlying mindfulness-based pain attenuation. Both treatment (focused-attention mindfulness vs sham) and instruction ("told mindfulness" vs "told sham") were manipulated in a balanced placebo design. Changes in acute heat pain were evaluated in 153 healthy adults randomized to receive 6 x 20 minutes of one of the four treatment by instruction interventions or no treatment. Participants receiving any intervention demonstrated improved pain outcomes (unpleasantness, intensity and tolerance) relative to no treatment. The instruction manipulation increased expectation for pain relief in those told mindfulness relative to told sham, but there were no main effects or interactions of treatment or instruction on pain outcomes. However, irrespective of actual intervention received, the belief of receiving mindfulness predicted increased pain threshold and tolerance, with expectancy fully mediating the effect on pain tolerance. These findings suggest a lack of specific effects of mindfulness and instruction on acute pain. Nonetheless, participants' expectancies and beliefs about the treatment they received did predict pain relief. Together with the overall improvement following any intervention, these findings suggest that expectancy and belief may play a stronger role in attenuating acute pain in novices following brief mindfulness interventions than the actual mindfulness-specific processes or instructions delivered.
Learn More >Individually unique dynamics of cortical connectivity reflect the ongoing intensity of chronic pain.
Chronic pain diseases are characterised by an ongoing and fluctuating endogenous pain, yet it remains to be elucidated how this is reflected by the dynamics of ongoing functional cortical connections.Here, we investigated the cortical encoding of 20 chronic back pain patients and 20 chronic migraineurs in four repeated fMRI sessions. A brain parcellation approach subdivided the whole brain into 408 regions. Linear mixed effects models were fitted for each pair of brain regions to explore the relationship between the dynamic cortical connectivity and the observed trajectory of the patients' ratings of fluctuating endogenous pain.Overall, we found that periods of high and increasing pain were predominantly related to low cortical connectivity. The change of pain intensity in chronic back pain was subserved by connections in left parietal opercular regions, right insular regions, as well as large parts of the parietal, cingular and motor cortices. The change of pain intensity direction in chronic migraine was reflected by decreasing connectivity between the anterior insular cortex and orbitofrontal areas, as well as between the PCC and frontal and ACC regions.Interestingly, the group results were not mirrored by the individual patterns of pain-related connectivity, which is suggested to deny the idea of a common neuronal core problem for chronic pain diseases. The diversity of the individual cortical signatures of chronic pain encoding results adds to the understanding of chronic pain as a complex and multifaceted disease. The present findings support recent developments for more personalised medicine.
Learn More >Following surgical repair after peripheral nerve injury, neuropathic pain diminishes in most patients, but can persist in a small proportion of cases the mechanism of which remains poorly understood. Based on the spared nerve injury (SNI), we developed a rat nerve repair (NR) model, where a delayed reconstruction of the SNI injured nerves resulted in alleviating chronic pain-like behavior only in a subpopulation of rats. Multiple behavioral measures were assayed over 11-week pre- and post-surgery periods (tactile allodynia, pain prick responses, sucrose preference, motor coordination, cold allodynia) in SNI (n=10), sham (n=8), and NR (n=12) rats. All rats also underwent resting-state- fMRI under anesthesia at multiple timepoints post-surgery, and at 10-weeks histology and retrograde labeling was used to calculate peripheral reinnervation. Behavioral measures indicated that at about 5-weeks post-surgery the NR group separated to pain persisting (NR-persisting, n=5) and recovering groups (NR-recovering, n=7). Counts of afferent nerves and of DRG cells were not different between NR groups. Therefore, NR group differences could not be explained by peripheral reorganization. In contrast, large brain functional connectivity differences were observed between NR groups, where corticolimbic reorganization paralleled with pain recovery (repeat measure ANOVA, false discovery rate, p <0.05), and functional connectivity between accumbens and medial frontal cortex was related both to tactile allodynia (nociception) and to sucrose preference (anhedonia) in NR group. Our study highlights the importance of brain circuitry in the reversal of neuropathic pain as a natural pain-relieving mechanism. Further studies regarding the therapeutic potentials of these processes are warranted.
Learn More >Malfunctioning synaptic plasticity is one of the major mechanisms contributing to the development of chronic pain. We studied spike-timing dependent depression (tLTD) in the ACC of male mice, a brain region involved in processing emotional aspects of pain. tLTD onto layer 5 pyramidal neurons depended on postsynaptic calcium-influx through GluN2B-containing NMDARs and retrograde signaling via nitric oxide to reduce presynaptic release probability. After chronic constriction injury of the sciatic nerve, a model for neuropathic pain, tLTD was rapidly impaired; and this phenotype persisted even beyond the time of recovery from mechanical sensitization. Exclusion of GluN2B-containing NMDARs from the postsynaptic site specifically at projections from the anterior thalamus to the ACC caused the tLTD phenotype, whereas signaling downstream of nitric oxide synthesis remained intact. Thus, transient neuropathic pain can leave a permanent trace manifested in the disturbance of synaptic plasticity in a specific afferent pathway to the cortex.Synaptic plasticity is one of the main mechanisms that contributes to the development of chronic pain. Most studies have focused on potentiation of excitatory synaptic transmission, but very little is known about the reduction in synaptic strength. We have focused on the ACC, a brain region associated with the processing of emotional and affective components of pain. We studied spike-timing dependent LTD, which is a biologically plausible form of synaptic plasticity, which depends on the relative timing of presynaptic and postsynaptic activity. We found a long-lasting and pathway-specific suppression of the induction mechanism for spike-timing dependent LTD from the anterior thalamus to the ACC, suggesting that this pathology might be involved in altered emotional processing in pain.
Learn More >The study investigated the cellular and molecular mechanisms in the peripheral nervous system (PNS) underlying the symptoms of urologic chronic pelvic pain syndrome (UCPPS) in mice. This work also aimed to test the feasibility of reversing peripheral sensitization in vivo in alleviating UCPPS symptoms. Intravesical instillation of vascular endothelial growth factor A (VEGFA) was used to induce UCPPS-like symptoms in mice. Spontaneous voiding spot assays and manual Von Frey tests were used to evaluate the severity of lower urinary tract symptoms (LUTS) and visceral hypersensitivity in VEGFA-instilled mice. Bladder smooth muscle strip contractility recordings (BSMSC) were used to identify the potential changes in myogenic and neurogenic detrusor muscle contractility at the tissue-level. Quantitative real-time PCR (qPCR) and fluorescent immunohistochemistry were performed to compare the expression levels of VEGF receptors and nociceptors in lumbosacral dorsal root ganglia (DRG) between VEGFA-instilled mice and saline-instilled controls. To manipulate primary afferent activity, Gi-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADD) were expressed in lumbosacral DRG neurons of TRPV1-Cre-ZGreen mice via targeted adeno-associated viral vector (AAVs) injections. A small molecule agonist of Gi-DREADD, clozapine-N-oxide (CNO), was injected into the peritoneum (i. p.) in awake animals to silence TRPV1 expressing sensory neurons in vivo during physiological and behavioral recordings of bladder function. Intravesical instillation of VEGFA in the urinary bladders increased visceral mechanical sensitivity and enhanced RTX-sensitive detrusor contractility. Sex differences were identified in the baseline detrusor contractility responses and VEGF-induced visceral hypersensitivity. VEGFA instillations in the urinary bladder led to significant increases in the mRNA and protein expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) in lumbosacral DRG, whereas the expression levels of transient receptor potential cation channel subfamily V member 1 (TRPV1) and VEGF receptors (VEGFR1 and VEGFR2) remained unchanged when compared to saline-instilled animals. Importantly, the VEGFA-induced visceral hypersensitivity was reversed by Gi-DREADD-mediated neuronal silencing in lumbosacral sensory neurons. Activation of bladder VEGF signaling causes sensory neural plasticity and visceral hypersensitivity in mice, confirming its role of an UCPPS biomarker as identified by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research studies. Pharmacogenetic inhibition of lumbosacral sensory neurons in vivo completely reversed VEGFA-induced pelvic hypersensitivity in mice, suggesting the strong therapeutic potential for decreasing primary afferent activity in the treatment of pain severity in UCPPS patients.
Learn More >The King Baboon spider, , is a burrowing African tarantula. Its impressive size and appealing coloration are tempered by reports describing severe localized pain, swelling, itchiness, and muscle cramping after accidental envenomation. Hyperalgesia is the most prominent symptom after bites from , but the molecular basis by which the venom induces pain is unknown. Proteotranscriptomic analysis of venom uncovered a cysteine-rich peptide, δ/κ-theraphotoxin-Pm1a (δ/κ-TRTX-Pm1a), that elicited nocifensive behavior when injected into mice. In small dorsal root ganglion neurons, synthetic δ/κ-TRTX-Pm1a (sPm1a) induced hyperexcitability by enhancing tetrodotoxin-resistant sodium currents, impairing repolarization and lowering the threshold of action potential firing, consistent with the severe pain associated with envenomation. The molecular mechanism of nociceptor sensitization by sPm1a involves multimodal actions over several ion channel targets, including Na1.8, K2.1, and tetrodotoxin-sensitive Na channels. The promiscuous targeting of peptides like δ/κ-TRTX-Pm1a may be an evolutionary adaptation in pain-inducing defensive venoms.
Learn More >Opioids are commonly prescribed for pain despite growing evidence of their low efficacy in the treatment of chronic inflammatory pain and the high potential for misuse. There is a clear need to investigate non-opioid alternatives for the treatment of pain. In the present study, we tested the hypothesis that acute and repeated dopamine agonist treatment would attenuate mechanical hypersensitivity in male Long-Evans rats experiencing chronic inflammatory pain. We used two clinically available therapeutics, l-DOPA (precursor of dopamine biosynthesis) and pramipexole (dopamine D2/3 receptor agonist), to examine the functional role of dopamine signaling on mechanical hypersensitivity using an animal model of chronic inflammatory pain (complete Freund's adjuvant, CFA). We found that both acute and repeated pramipexole treatment attenuated hyperalgesia-like behavior in CFA-treated animals but exhibited no analgesic effects in control animals. In contrast, there was no effect of acute or repeated l-DOPA treatment on mechanical hypersensitivity in either CFA- or saline-treated animals. Notably, we discovered some extended effects of l-DOPA and pramipexole on decreasing pain-like behavior at three days and one week post-drug treatment. We also examined the effects of pramipexole treatment on glutamatergic and presynaptic signaling in pain- and reward-related brain regions including the nucleus accumbens (NAc), dorsal striatum (DS), ventral tegmental area (VTA), cingulate cortex (CC), central amygdala (CeA), and periaqueductal gray (PAG). We found that pramipexole treatment decreased AMPA receptor phosphorylation (pGluR1845) in the NAc and DS but increased pGluR1845 in the CC and CeA. A marker of presynaptic vesicle release, pSynapsin, was also increased in the DS, VTA, CC, CeA, and PAG following pramipexole treatment. Interestingly, pramipexole increased pSynapsin in the NAc of saline-treated animals, but not CFA-treated animals, suggesting blunted presynaptic vesicle release in the NAc of CFA-treated animals following pramipexole treatment. To examine the functional implications of impaired presynaptic signaling in the NAc of CFA animals, we used ex vivo electrophysiology to examine the effects of pramipexole treatment on the intrinsic excitability of NAc neurons in CFA- and saline-treated animals. We found that pramipexole treatment reduced NAc intrinsic excitability in saline-treated animals but produced no change in NAc intrinsic excitability in CFA-treated animals. These findings indicate alterations in dopamine D2/3 receptor signaling in the NAc of animals with a history of chronic pain in association with the anti-hyperalgesic effects of pramipexole treatment.
Learn More >Capable of reflecting the location and intensity of external harmful stimuli, a nociceptor network is of great importance for receiving pain-perception information. However, the hardware-based implementation of a nociceptor network through the use of a transistor array remains a great challenge in the area of brain-inspired neuromorphic applications. Herein, a simple ionotronic junctionless oxide transistor array with pain-perception abilities is successfully realized due to a coplanar-gate proton-coupling effect in sodium alginate biopolymer electrolyte. Several important pain-perception characteristics of nociceptors are emulated, such as a pain threshold, the memory of prior injury, and sensitization behavior due to pathway alterations. In particular, a good graded pain-perception network system has been successfully established through coplanar capacitance and resistance. More importantly, clear polarity reversal of Lorentz-type spatiotemporal pain-perception emulation can be finally realized in our projection-dependent nociceptor network. This work may provide new avenues for bionic medical machines and humanoid robots based on these intriguing pain-perception abilities.
Learn More >This exploratory study investigates if intra-articular injected gold microparticles in knee osteoarthritis (KOA) reduce immunomodulatory-based pain via proteomic changes in the synovial fluid (SF) and serum.
Learn More >Bone cancer pain (BCP) seriously affects the quality of life, however, due to its complex mechanism the clinical treatment was unsatisfactory. Recent studies have showed several Rac-specific guanine nucleotide exchange factor (GEF) that affect development and structure of neuronal processes play a vital role in the regulation of chronic pain. P-Rex2 is one of GEFs that regulate spine density, and the present study was performed to examine the effect of P-Rex2 on the development of BCP. Tumor cells implantation induced the mechanical hyperalgesia, which was accompanied by an increase in spinal protein P-Rex2, phosphorylated Rac1 (p-Rac1) and phosphorylated GluR1 (p-GluR1), and number of spines. Intrathecal injection a P-Rex2-targeting RNAi lentivirus relieved BCP and reduced the expression of P-Rex2, p-Rac1, p-GluR1and number of spines in the BCP mice. Meanwhile, P-Rex2 knockdown reversed BCP-enhanced AMPA receptor (AMPAR)-induced current in dorsal horn neurons. In summary, this study suggested that P-Rex2 regulated GluR1-containing AMPAR trafficking and spine morphology via Rac1/pGluR1 pathway is a fundamental pathogenesis of BCP. Our findings provide a better understanding of the function of P-Rex2 as a possible therapeutic target for relieving BCP.
Learn More >Prior studies identified iron deposition in deep brain nuclei and the periaqueductal gray matter region in chronic migraine (CM), and less is known about the cerebral iron deposition over the whole cerebral gray matter in CM. The aim of this case-control study is to investigate the cerebral iron deposition of gray matter in CM using an advanced quantitative susceptibility mapping.
Learn More >Tumor metastasis to bone is often accompanied by a severe pain syndrome (cancer-induced bone pain, CIBP) that is frequently unresponsive to analgesics, which markedly reduces patient quality of life and cancer treatment tolerance in patients. Prolonged pain can induce hypersensitivity via spinal plasticity, and several recent studies have implicated the involvement of vascular endothelial growth factor-A (VEGF-A) signaling in this process. Here, we speculated that CIBP is associated VEGF-A/VEGFR2 signaling could in the spinal cord. A mouse model of CIBP was established by intramedullary injection of Lewis lung carcinoma (LLC) cells in the mouse femur. Pain sensitization and potential amelioration via VEGF-A/VEGFR2 blockade were measured using paw withdrawal threshold to mechanical stimulation and paw withdrawal latency to thermal. Spinal VEGF-A/VEGFR2 signaling was blocked by intrathecal injection of the VEGF-A antibody or the specific VEGFR2 inhibitor ZM323881. Changes in the expression levels of VEGF-A, VEGFR2, and other pain-related signaling factors were measured using western blotting and immunofluorescence staining. Mice after LLC injection demonstrated mechanical allodynia and thermal hyperalgesia, both of which were suppressed via anti-VEGF-A antibody or ZM323881. Conversely, the intrathecal injection of exogenous VEGF-A was sufficient to cause pain hypersensitivity in naïve mice via the VEGFR2-mediated activation of protein kinase C. Moreover, the spinal blockade of VEGF-A or VEGFR2 also suppressed N-methyl-D-aspartate receptor (NMDAR) activation and downstream Ca2+-dependent signaling. Thus, spinal VEGF-A/VEGFR2/NMDAR signaling pathways may be critical mediators of CIBP.
Learn More >Offset analgesia is defined by a dramatic drop in perceived pain intensity with a relatively small decrease in noxious input. Although functional magnetic resonance imaging studies implicate subcortical descending inhibitory circuits during offset analgesia, the role of cortical areas remains unclear. The current study identifies cortical correlates of offset analgesia using functional near infrared spectroscopy (fNIRS). Twenty-four healthy volunteers underwent fNIRS scanning during offset (OS) and control (Con) heat stimuli applied to the forearm. After controlling for non-neural hemodynamic responses in superficial tissues, widespread increases in cortical oxygenated hemoglobin concentration were observed, reflecting cortical activation during heat pain. OS – Con contrasts revealed deactivations in bilateral medial prefrontal cortex (mPFC) and bilateral somatosensory cortex (SSC) associated with offset analgesia. Right dorsolateral prefrontal cortex (dlPFC) showed activation only during OS. These data demonstrate opposing cortical activation patterns during offset analgesia and support a model in which right dlPFC underlies ongoing evaluation of pain intensity change. With predictions of decreasing pain intensity, right dlPFC activation likely inhibits ascending noxious input via subcortical pathways resulting in SSC and mPFC deactivation. This study identifies cortical circuitry underlying offset analgesia and introduces the use of fNIRS to study pain modulation in an outpatient clinical environment.
Learn More >Bupivacaine, a local anaesthetic, is widely applied in the epidural or subarachnoid space to clinically manage acute and chronic pain. However, the underlying mechanisms are complex and unclear. Glycine transporter 1 (GlyT1) in the spinal cord plays a critical role in various pathologic pain conditions. Therefore, we sought to determine whether bupivacaine exerts its analgesic effect by regulating GlyT1 expression and to determine the underlying mechanisms of regulation. Primary astrocytes prepared from the spinal cord of rats were treated with bupivacaine. The protein levels of GlyT1, brain-derived neurotrophic factor (BDNF) and phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase α (p-AMPKα) were measured by western blotting or immunofluorescence. In addition, 7,8-dihydroxyflavone (7,8-DHF, BDNF receptor agonist) and AMPK shRNA were applied to verify the relationship between the regulation of GlyT1 by bupivacaine and the p-AMPKα/BDNF signalling pathway. After treatment with bupivacaine, GlyT1 expression was diminished in a concentration-dependent manner, while the expression of BDNF and p-AMPK was increased. Moreover, 7,8-DHF decreased GlyT1 expression, and AMPK knockdown suppressed the upregulation of BDNF expression by bupivacaine. Finally, we concluded that bupivacaine reduced GlyT1 expression in spinal astrocytes by activating the p-AMPKα/BDNF signalling pathway. These results provide a new mechanism for the analgesic effect of intrathecal bupivacaine in the treatment of acute and chronic pain.
Learn More >Research on placebo analgesia usually shows that people experienced a reduction in pain after using a placebo analgesic. An emerging line of research argues that, under some circumstances, merely possessing (but not using) a placebo analgesic could induce placebo analgesia. The current study investigates how temporary expectation of pain reduction associated with different forms of possessing a placebo analgesic affects pain outcomes. Healthy participants (n = 90) were presented with a vial of olive oil (placebo), described as a blended essential oil that blocks pain sensations upon nasal inhalation, and were asked to anticipate the benefits of such analgesic oil to the self (such as anticipating the analgesic oil to reduce their pain). Participants were randomized into one of three different possession conditions: physical-possession condition (participants possessed a tangible placebo analgesic oil, inducing an expectation to acquire analgesic benefit early upon the experience of pain), psychological-possession condition (participants possessed a coupon, which can be redeemed for a placebo analgesic oil, inducing an expectation to acquire analgesic benefit later upon the experience of pain), or no-possession condition. Participants did a cold pressor test (CPT) to experience experimentally-induced pain on their non-dominant hand. Their objective physical pain responses (pain-threshold and pain-tolerance), and subjective psychological pain perception (pain intensity, severity, quality, and unpleasantness) were measured. Results revealed that participants in the physical-possession condition reported greater pain-threshold, F(2, 85) = 6.65, p = 0.002, and longer pain-tolerance, F(2, 85) = 7.19, p = 0.001 than participants in the psychological-possession and no-possession conditions. No significant group difference was found in subjective pain perception. The results of this study can advance knowledge about pain mechanisms and novel pain management.
Learn More >Conservative management of cervical radiculopathy (CR) is a first treatment option as the risk-benefit ratio for surgery is less favorable. Systematic reviews and clinical practice guidelines reporting on the effectiveness of nonsurgical management have not considered the timing of management. The aim of this study was to establish consensus on effective nonsurgical treatment modalities at different stages (ie, acute, subacute or chronic) of CR, using the Delphi method approach.
Learn More >Effective, rigorously evaluated nonpharmacological treatments for chronic pain are needed. This study compared the effectiveness of training in hypnosis (HYP) and mindfulness meditation (MM) to an active education control (ED). Veterans (N=328) were randomly assigned to 8 manualized, group-based, in-person sessions of HYP (n = 110), MM (n = 108), or ED (n = 110). Primary (average pain intensity; API) and secondary outcomes were assessed at pretreatment, posttreatment, and 3- and 6-months posttreatment. Treatment effects were evaluated using linear regression, a generalized estimating equation approach, or a Fisher exact test, depending on the variable. There were no significant omnibus between-group differences in pre- to posttreatment change in API, however pre- to posttreatment improvements in API and several secondary variables were seen for participants in all three conditions. Participation in MM resulted in greater decreases in API and pain interference at 6-months posttreatment relative to ED. Participation in HYP resulted in greater decreases in API, pain interference, and depressive symptoms at 3- and 6-months posttreatment compared to ED. No significant differences on outcomes between HYP and MM were detected at any time point. This study suggests that all three interventions provide posttreatment benefits on a range of outcomes, but the benefits of HYP and MM continue beyond the end of treatment, while the improvements associated with ED dissipate over time. Future research is needed to determine whether the between-group differences that emerged posttreatment are reliable, whether there are benefits of combining treatments, and to explore moderating and mediating factors.
Learn More >As the resident immune cells in the central nervous system, microglia play an important role in the maintenance of its homeostasis. Dysregulation of microglia has been associated with the development and maintenance of chronic pain. However, the relevant molecular pathways remain poorly defined. In this study, we used a mass spectrometry-based proteomic approach to screen potential changes of histone protein modifications in microglia isolated from the brain of control and cisplatin-induced neuropathic pain adult C57BL/6J male mice. We identified several novel microglial histone modifications associated with pain including statistically significantly decreased histone H3.1 lysine 27 mono-methylation (H3.1K27me1, 54.8% of control) and lysine 56 tri-methylation (7.5% of control), as well as a trend suggesting increased histone 3 tyrosine 41 nitration. We further investigated the functional role of H3.1K27me1 and found that treatment of cultured microglial cells for 4 consecutive days with 1-10 μM of NCDM-64, a potent and selective inhibitor of lysine demethylase 7A, an enzyme responsible for the demethylation of H3K27me1, dose-dependently elevated its levels with a greater than a 2-fold increase observed at 10 μM compared to vehicle-treated control cells. Moreover, pre-treatment of mice with NCDM-64 (10 or 25 mg/kg/day, i.p.) prior to cisplatin treatment prevented the development of neuropathic pain in mice. The identification of specific chromatin marks in microglia associated with chronic pain may yield critical insight into the contribution of microglia to the development and maintenance of pain, and opens new avenues for the development of novel non-opioid therapeutics for the effective management of chronic pain. This article is protected by copyright. All rights reserved.
Learn More >There is limited research on how the opioid epidemic and consequent risk reduction policies have impacted pain management among cancer patients. The purpose of this study is to analyze how an Opioid Safety Initiative (OSI) implemented at the Veteran's Health Administration (VHA) affected opioid prescribing patterns and opioid-related toxicity.
Learn More >Juvenile fibromyalgia (JFM) is a prevalent chronic pain condition affecting children and adolescents worldwide during a critical period of brain development. To date, no published studies have addressed the pathophysiology of JFM. Here we characterize gray matter volume (GMV) alterations in JFM patients for the first time and investigate their functional and clinical relevance.
Learn More >The ObserVational survey of the Epidemiology, tReatment and Care of MigrainE (OVERCOME; United States) study is a multicohort, longitudinal web survey that assesses symptomatology, consulting, diagnosis, treatment, and impact of migraine in the United States.
Learn More >Bone cancer pain (BCP) is the most frequently observed chronic cancer pain, and its development remains largely unexplored. Dysregulation of non-coding RNAs greatly contributes to the pathogenesis of BCP. In the present study, we found a new long noncoding RNA (lncRNA), NONRATT009773.2, and investigated its role in the spinal cord of BCP rats. Our results showed that NONRATT009773.2 was significantly up-regulated in BCP model rats, while depletion of NONRATT009773.2 attenuated BCP. In contrast, overexpression of NONRATT009773.2 triggered pain-like symptoms in normal animals. Moreover, NONRATT009773.2 functioned as a microRNA (miRNA) sponge to absorb miR-708-5p and up-regulated miRNA downstream target CXCL13, which plays fundamental roles in the initiation and maintenance of neuroinflammation and hyperalgesia. Collectively, our current findings indicated that NONRATT009773.2 could be employed as a new therapeutic target for BCP.
Learn More >This study retrospectively studied the incidence of chronic post-surgical pain (CPSP) following single-stage implant-based breast reconstruction (IBBR) and evaluated the possible risk factors. This was a retrospective cohort study, involving all patients undergoing single-stage IBBR between January and December 2019. The follow-up was completed between January and March 2021. The scores for satisfaction (SS) were based on the BREAST-Q, while the pain burden index (PBI) was used to assess the degree of CPSP. The questionnaires were completed by 159 patients. CPSP occurred in 48.43% of the patients, 2.52% of them being severe cases. Significant predictors for the development of CPSP in the univariate analysis included severe acute postoperative pain (PP), a history of preoperative chronic pain, psychological disorders, SS with the reconstructed breasts, and whether there were any regrets about having had the reconstruction. Multivariate analysis identified severe acute PP (odds ratio (OR) = 2.80, 95% confidence interval (CI) = 1.16-6.79, p = 0.023), a history of preoperative chronic pain (OR = 3.39, 95% CI = 1.42-8.10, p = 0.006), and the SS (OR = 0.86, 95% CI = 0.75-0.99, p = 0.034) as being independently associated with the development of CPSP. In subgroup analysis, the PBI of the patients in the SS < 12 group (p < 0.001), the bilateral group (p < 0.01), and the severe acute PP group (p < 0.005) was significantly higher than the PBI of those in the control groups. This study demonstrated a significant incidence of CPSP following single-stage IBBR, and the patients with lower SS of their reconstructed breasts developed more CPSP. Lower SS, bilateral procedures, and severe acute PP were predictors of higher PBI.Trial registration: Registered in Chictr.org.cn registry system on 24 February 2020 (ChiCTR2000030139).
Learn More >Postoperative pain is a common clinical problem that, in preclinical studies, has almost exclusively been studied in males. Altered C-fibre activity-dependent slowing (ADS) is a potential underlying mechanism, given it is altered after tissue inflammation and nerve injury, but this has not been explored post-incision. We therefore investigated the effect of hind-paw incision on C-fibre ADS in both sexes and the involvement of voltage-gated sodium channels (Na) as they contribute to ADS. We also assessed mechanical and thermal sensitivity post-incision in both sexes.
Learn More >This ecological momentary assessment (EMA) study examined the extent of pain intensity variability among 140 individuals with chronic low back pain and explored predictors of such variability and psychosocial and health care utilization outcomes. Individuals completed momentary pain intensity reports (0-10 numeric rating scale) several times daily for two periods of seven consecutive days, one month apart. Participants also completed online questionnaires at baseline which tapped into pain characteristics, pain-related catastrophization, kinesiophobia, activity patterns, and depression and anxiety symptoms. Questionnaires assessing quality of life and health care utilization were administered online one month after completion of the last EMA report. Data were analyzed using linear hierarchical location-scale models. Results showed that pain intensity fluctuated over the course of a week as shown by an average standard deviation of 1.2. The extent of variability in pain intensity scores was heterogeneous across participants but stable over assessment periods. Patients' baseline characteristics along with psychosocial and health care utilization outcomes were not significantly associated with pain intensity variability. We conclude that pain intensity variability differs across patients yet correlates remain elusive. There is an important gap in our knowledge of what affects this variability. Future EMA studies should replicate and extend current findings.
Learn More >The increased prevalence of temporomandibular joint osteoarthritis (TMJOA) in children and adolescents has drawn considerable attention as it may interfere with mandibular condyle growth, resulting in dento-maxillofacial deformities. However, treatments for osteoarthritis have been ineffective at restoring the damaged bone and cartilage structures due to poor understanding of the underlying degenerative mechanism. In this study, we demonstrate that Gli1 cells residing in the subchondral bone contribute to bone formation and homeostasis in the mandibular condyle, identifying them as osteogenic progenitors in vivo. Furthermore, we show that, in a TMJOA mouse model, derivatives of Gli1+ cells undergo excessive expansion along with increased but uneven distribution of osteogenic differentiation in the subchondral bone, which leads to abnormal subchondral bone remodeling via Hedgehog (Hh) signaling activation and to the development of TMJOA. The selective pharmacological inhibition and specific genetic inhibition of Hh signaling in Gli1 osteogenic progenitors result in improved subchondral bone microstructure, attenuated local immune inflammatory response in the subchondral bone, and reduced degeneration of the articular cartilage, providing in vivo functional evidence that targeting Hh signaling in Gli1 osteogenic progenitors can modulate bone homeostasis in osteoarthritis and provide a potential approach for treating TMJOA.
Learn More >The main aim of this study was to assess the efficacy of exercise and manual therapy interventions in patients with primary headache through systematic review.
Learn More >To evaluate veteran patient and provider perceptions and preferences on complementary and integrative medicine (CIM) for headache management.
Learn More >To compare clinical features and treatments of patients with systemic juvenile idiopathic arthritis (sIJA) and adult-onset Still's disease (AOSD).
Learn More >Chronic pain is a pervasive health problem and is associated with tremendous socioeconomic costs. However, current pain treatments are often ineffective due, in part, to the multi-factorial nature of pain. Mild hypohydration was shown to increase experimental pain sensitivity in men, but whether this also occurs in women has not been examined. Fluctuations in ovarian hormones (i.e., 17ß-oestradiol and progesterone) throughout the menstrual cycle may influence a woman's pain sensitivity, as well as hydration levels, suggesting possible interactions between hypohydration and menstrual phase on pain. We investigated the effects of mild hypohydration (HYPO, 24 hr of fluid restriction) on ischaemic pain sensitivity in 14 eumenorrheic women during the early follicular (EF) and mid-luteal (ML) phases of their menstrual cycle. We also examined whether acute water ingestion could reverse the negative effects of hypohydration. Elevated serum osmolality, plasma copeptin, and urine specific gravity indicated mild hypohydration. Compared to euhydration, HYPO reduced pain tolerance (by 34 ± 46 s; P = 0.02, ηp = 0.37) and increased ratings of pain intensity (by 0.7 ± 0.7 cm; P = 0.004; ηp = 0.55) and unpleasantness (by 0.7 ± 0.9 cm; P = 0.02; ηp = 0.40); these results were not influenced by menstrual phase. Water ingestion reduced thirst perception (Visual Analogue Scale, by 2.3 ± 0.9 cm; P < 0.001, ηp = 0.88) but did not reduce pain sensitivity. Therefore, hypohydration increases pain sensitivity in women with no influence of menstrual phase.
Learn More >Pain-related fear (PRF) can be a significant factor contributing to the development and maintenance of pain-related disability in individuals with persistent pain. One treatment approach to target PRF and related avoidance-behavior is exposure in vivo (EXP). EXP has a long history in the field of anxiety, a field that is constantly evolving. This Perspective outlines recent theoretical advancements and how they apply to EXP for PRF, including suggestions for how to optimize inhibitory learning during EXP; reviews mechanistic work from neuroimaging supporting the targeting of PRF in people with chronic pain; and focuses on clinical applications of EXP for PRF, as EXP is moving into new directions regarding who is receiving EXP (eg, EXP in chronic secondary pain) and how treatment is provided (EXP in primary care with a crucial role for physical therapists). Considerations are provided regarding challenges, remaining questions, and promising future perspectives.
Learn More >Chronic itch can severely affect quality of life. Patients report that their chronic itch can be exacerbated by exposure to warm conditions ("warmth hyperknesis"). The aim of this mechanistic study was to investigate the effect of mild heating of the skin in humans on various experimental models of itch. A total of 18 healthy subjects were recruited to the study. Itch was provoked by histamine, serotonin, or cowhage in 3 different sessions. The provoked area was heated with an infrared lamp, and the skin temperature was either not altered, or was increased by 4°C or 7°C. Subsequent to induction of itch, the itch intensity was recorded for 10 min while the skin was heated continuously throughout the entire period of itch induction. Heating the skin resulted in a significant increase in itch intensity when provoked by histamine or serotonin. It is possible that thermoception and pruriception interact and selectively produce a higher itch intensity in histaminergic and serotoninergic itch.
Learn More >Diabetes mellitus and its consequences continue to put a significant demand on medical resources across the world. Diabetic neuropathic pain (DNP) is a frequent diabetes mellitus chronic microvascular outcome. Allodynia, hyperalgesia, and aberrant or lack of nerve fibre sensation are all symptoms of DNP. These clinical characteristics will lead to worse quality of life, sleep disruption, depression, and increased mortality. Although the availability of numerous medications that alleviate the symptoms of DNP, the lack of long-term efficacy and unfavourable side effects highlight the urgent need for novel treatment strategies. This review paper systematically analysed the preclinical research on the treatment of DNP using plant phytochemicals that contain only tannins. A total of 10 original articles involved in and experiments addressing the promising benefits of phytochemical tannins on DNP were examined between 2008 and 2021. The information given implies that these phytochemicals may have relevant pharmacological effects on DNP symptoms through their antihyperalgesic, anti-inflammatory, and antioxidant properties; however, because of the limited sample size and limitations of the studies conducted so far, we were unable to make definitive conclusions. Before tannins may be employed as therapeutic agents for DNP, more study is needed to establish the specific molecular mechanism for all of these activities along the pain pathway and examine the side effects of tannins in the treatment of DNP.
Learn More >Despite the wide variety of Covid-19 symptoms, pain and the related mechanisms underlying unsettled nociceptive status is still under-prioritized. Understanding the complex network of Covid-19-related pain may result in new lines of study. It is unknown whether patient's immunological background influence pain in the acute phase of Covid-19, including musculoskeletal pain. Thus, we evaluated the blood levels of selected molecules that are upregulated in SARS-CoV-2 infection and analyzed a possible correlation with pain during Covid-19.
Learn More >The STarT Back Tool (SBT) predicts risk for persistent low back pain (LBP)-related disability based on psychological distress levels. Other non-psychological factors associated with LBP, such as pain sensitivity and physical performance, may further characterize SBT risk subgroups. The purpose of this study was to determine whether a low risk SBT subgroup demonstrated lower pain sensitivity and/or higher physical performance compared to a medium/high risk SBT subgroup.
Learn More >One in 5 adults in the United States live with a mental illness, and many more struggle with stress-related chronic illnesses. Physical therapists often see the physical effects that stress has on the body, but there is an underutilization of evidence-based stress management strategies with patients and clients. Mindfulness-and-acceptance-based interventions (MABIs) constitute a family of methods that emphasize present-moment awareness, nonjudgment, and values-based living. They operate by teaching patients to cope with stressful thoughts, emotions, and physical sensations. MABIs are associated with improved health outcomes in areas commonly seen in physical therapist practice, including health promotion, physical function, injury prevention, pain management, immune function, and noncommunicable diseases. The purpose of this Perspective article is to (1) describe MABIs, (2) discuss the relevance of MABIs to physical therapist practice, (3) discuss the positive impact of MABIs for pain, sports, immune function, physical and mental health promotion and wellness, and (4) identify MABI outcome measures related to health behavior change. It is time.
Learn More >A comprehensive analysis of clinical information in patients with chronic low back pain (CLBP) was performed to clarify the clinical characteristics of geriatric LBP from the perspective of body composition, spinal alignment, and blood findings related to senescence. We enrolled 203 patients with an average age of 79.0 years (77 men and 126 women), with non-specific CLBP as a single-center prospective cohort study, the patients were compared with age- and sex-matched controls without CLBP using a propensity score-matching. We performed laboratory analysis, radiographic evaluations for global spinal parameter and lumbar degeneration, and body composition analysis using whole-body dual-energy X-ray absorptiometry. We observed a higher red blood cell distribution width (RDW) (p < 0.001), which is an index of aging, as well as a lower vitamin D level (p = 0.002), skeletal muscle mass index (p = 0.045) and a higher fat mass (p = 0.007) in patients with CLBP. Moreover, patients with geriatric CLBP had significantly lower lumbar lordosis (p = 0.024), and higher sagittal vertical axis (p = 0.006) was correlated with lower extremity and trunk muscle mass (p < 0.001), independent of lumbar degeneration. Geriatric patients with CLBP have sarcopenic fat accumulation and spinal sagittal malalignment with senescent status, such as elevated RDW and hypovitaminosis D.
Learn More >Dysfunction of the cingulo-frontal-parietal (CFP) cognitive attention network has been associated with the pathophysiology of chronic low back pain (cLBP). However, the direction of information processing within this network remains largely unknown. We aimed to study the effective connectivity among the CFP regions in 36 cLBP patients and 36 healthy controls by dynamic causal modeling (DCM). Both the resting-state and task-related (Multi-Source Interference Task, MSIT) functional magnetic resonance imaging (fMRI) data were collected and analyzed. The relationship between the effective connectivity of the CFP regions and clinical measures was also examined. Our results suggested that cLBP had significantly altered resting-state effective connectivity of the prefrontal cortex (PFC)-to-mid-cingulate cortex (MCC) (increased) and MCC-to-left superior parietal cortex (LPC) (decreased) pathways as compared with healthy controls. MSIT-related DCM suggested that the interference task could significantly increase the effective connectivity of the right superior parietal cortex (RPC)-to-PFC and RPC-to-MCC pathways in cLBP than that in healthy controls. The control task could significantly decrease the effective connectivity of the MCC-to-LPC and MCC-to-RPC pathways in cLBP than that in healthy controls. The endogenous connectivity of the PFC-to-RPC pathway in cLBP was significantly lower than that in healthy controls. No significant correlations were found between the effective connectivity within CFP networks and pain/depression scores in patients with cLBP. In summary, our findings suggested altered effective connectivity in multiple pathways within the CFP network in both resting-state and performing attention-demanding tasks in patients with cLBP, which extends our understanding of attention dysfunction in patients with cLBP.
Learn More >Post-burn pruritus is a significant issue that can have a devastating impact on patient quality of life. Despite its known negative impact, few studies have focused on the pediatric population. Thus, the aim of this study was to determine the incidence of pruritus among pediatric burn patients as well as identify its predictive factors and commonly used treatments, including the novel use of laser therapy. A retrospective analysis of all burn patients treated at our pediatric burn centre from 2009 to 2017 was conducted. The primary outcome measure was the presence or absence of pruritus at any point following the burn. One thousand seven hundred and eighty-three patients met the inclusion criteria for this study. The mean age at injury was 3.67 years (SD 4.02) and the mean burn TBSA was 3.48% (SD 4.81) with most burns resulting from scalds (66%). In total, 665 patients (37.3%) experienced pruritus. Following multivariable logistic regression, TBSA, age > 5 years, burns secondary to fire/flames, and burn depth, were identified as significant predictors of pruritus (p < 0.05). Pruritus was treated with diphenhydramine (85.0%), hydroxyzine (37.3%), and gabapentin (4.2%) as well as massage (45.7%), pressure garments (20.0%), and laser therapy (8.6%). This study addresses the knowledge gap in literature related to post-burn pruritus among pediatric patients and includes one of the largest patient cohorts published to date. Moreover, the results further contribute to our understanding of post-burn pruritus in children and may help us to predict which patients are most likely to be affected, so that treatment can be initiated as soon as possible.
Learn More >Telementoring is an evidence-based approach to meet the educational needs of primary care providers (PCPs) and to improve the quality of chronic pain care. This mixed methods study evaluated the effectiveness of pain management telementoring in improving provider knowledge, attitudes, and perceived competence.
Learn More >The purpose of this study was to propose a definition of "wearing off" at the individual patient-level and determine the percentage of patients with migraine who experience "wearing off" of efficacy of galcanezumab at the end of a treatment cycle using this predefined threshold.
Learn More >Central post stroke pain (CPSP) is an intractable neuropathic pain syndrome that occurs after the acute focal lesion of the central nervous system (CNS) due to a cerebrovascular cause. Epoxyeicosatrienoic acids (EETs) exert many pharmacological effects in vivo and in vitro, such as anti-apoptosis, anti-inflammatory, and anti-oxidative stress. Neuroinflammation and apoptosis are the potential pathophysiological mechanisms of neuropathic pain. This study aimed to investigate whether 14,15-EET has an antinociception effect on CPSP rats through its anti-inflammation and anti-apoptosis mechanisms. Rats were treated with type IV collagenase (CPSP group) or saline (Sham group) via injection with a Hamilton syringe into the ventral posterior lateral nucleus (VPL) according to the stereotaxic coordinates. We first tested the mechanical withdrawal threshold, as well as neuroinflammation- and apoptosis-related protein expressions in the per-lesion site of CPSP and Sham rats. Sprague-Dawley rats were randomly divided into five groups, as follows: vehicle; EET at 0.025, 0.05, and 0.1 μg; and EET (0.1 μg) + EEZE (3.25 ng). EET or and vehicle were administered into VPL nuclei three consecutive days after hemorrhagic stroke. Immunostaining, ELISA, and Western blot were performed to evaluate neuroinflammation and apoptosis. Hemorrhagic stroke induced mechanical allodynia, glial activation, neuroinflammation, and apoptosis-related protein upregulation. However, early treatment with 14,15-EET inhibited glial cell activation, decreased proinflammatory cytokines and apoptosis-related protein, and alleviated the pain behavior of CPSP rats. Our results provided strong evidence that antinociception produced by 14,15-EET is partly mediated by the inhibition of neuroinflammation and apoptosis.
Learn More >As the relay centre for processing sensory information, the thalamus may involve in the abnormal sensory procedure caused by cortical spreading depression (CSD). However, few studies have focused on the transient response of thalamus during CSD. Our study aimed to investigate the neuronal activity of mouse thalamus ventral posteromedial nucleus (VPM) during CSD by in vivo micro-endoscopic fluorescence imaging of the genetic calcium probe GCaMP6s expressed in excitatory glutamatergic neurons.
Learn More >Breathlessness and pain frequently co-occur in chronic conditions, and their unpredictability is often reported to amplify perception and negative affect (NA), however any common neural mechanisms remain largely unexplored. This study examined the effects of (unpredictable) bodily threat on perception and neural gating of respiratory and somatosensory stimuli. Healthy adults (N=51) experienced brief paired inspiratory occlusions and electrocutaneous stimuli, with their neural activity monitored via electroencephalography. Neural gating was measured as a ratio of the N1 response to the second relative to the first stimulus in a pair. In 4/6 blocks, threatening stimulation, in form of additional loaded breaths or electrocutaneous pulses, was presented predictably or unpredictably. Participants reported: perceived intensity and unpleasantness of all stimuli, fear, trait NA and intolerance of uncertainty (IU). Threatening stimulation increased perception, fear, and N1 amplitudes, without affecting neural gating. There was no group effect of unpredictability, though interactions were found with NA and IU. Cross-modal correlations revealed significant baseline relationships in neural gating and perception, though not in their modulation by threat. The present findings demonstrate that respiratory and somatosensory modalities relate in baseline perception and neural gating, and exhibit similar modulation effects by unpleasant stimulation, with significant changes in perception but not gating. Further research is encouraged to elucidate the underlying mechanisms of these relationships, and the potential interactions with stimulus unpredictability.
Learn More >Novel externally powered spinal cord stimulation technology can be fully implanted when trialing the effectiveness of the therapy, since no percutaneous leads are needed, and the trial period lasted 30 days. Multiple tests of different stimulation modalities and parameters are possible, thus improving the chances that the therapy will lead to effective pain reduction.
Learn More >Lumbar facet joint syndrome (LFJS) has been suggested to be a main source of low back pain. Methylene blue (MB), an inhibitor of nitric oxide synthesis with potential analgesic and anti-inflammatory properties, has been widely applied for a variety of pain-related diseases. However, no studies have been conducted on the treatment of LFJS patients using MB.
Learn More >Interventions for chronic discogenic spine pain are currently insufficient in lowering individual patient suffering and global disease burden. A 2016 study of platelet rich plasma (PRP) for chronic discogenic pain previously demonstrated clinically significant response among active group patients compared with controls.
Learn More >Chronic neck and shoulder pain (CNSP) is a common neurological disorder, which females are more likely to suffer from. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. This study aimed to investigate altered PAG-based functional connectivity (FC) in female patients with CNSP related to healthy controls (HCs) and the effect of acupuncture for female patients with CNSP using PAG-based FC biomarkers.
Learn More >Glutamate, as well as nerve growth factor (NGF), is involved in nociception from peripheral tissues, such as muscles. However, the potential interaction between glutamate and NGF still remains unclear. This study investigated the interaction between glutamate-induced masseter muscle pain and NGF-induced allodynia on pain perception and jaw function in healthy individuals, and any possible sex differences in the response. Thirty pain-free adult participants (15 men and 15 women, mean age ± : 24 ± 4 years) participated in this study consisting of three sessions (Day 0, Day 3, and Day 4). NGF (5 μg/mL, 1.0 mL) was injected into the masseter muscle on Day 0 to induce muscle allodynia. On Day 3, glutamate (1M, 0.2 mL) was injected into the same masseter muscle. Before and after injections on Day 0 and 3, and post-injection (Day 4), spontaneous pain, temporal summation pain, as well as functional pain and fatigue in response to chewing were assessed with validated scales, and the pressure pain threshold (PPT) was recorded. Spontaneous pain intensity was significantly higher after glutamate than NGF ( < 0.001). PPTs, temporal summation pain and functional measures were all reduced 3 days after NGF injection ('s < 0.001). Injection of glutamate on Day 3 did not further affect PPTs or temporal summation pain and there were no sex differences in the effects ( > 0.189). Chewing pain ( = 0.022) and fatigue increased after glutamate injection to a higher degree in the women than men ( = 0.037). Taken together, while glutamate injected into the NGF-sensitized muscle was painful, it did not alter muscle tenderness in women vs. men. However, pain and fatigue evoked by jaw function were higher in women after glutamate injection. This suggest that sex differences reported for masseter myalgia, mimicked by glutamate and NGF mediated pain in this study, may be greater for measures of perceived jaw function, which should be considered in a clinical evaluation.
Learn More >Thigmotaxis is an innate predator avoidance behaviour of rodents and is enhanced when animals are under stress. It is characterised by the preference of a rodent to seek shelter, rather than expose itself to the aversive open area. The behaviour has been proposed to be a measurable construct that can address the impact of pain on rodent behaviour. This systematic review will assess whether thigmotaxis can be influenced by experimental persistent pain and attenuated by pharmacological interventions in rodents.
Learn More >Orofacial pain is a complex disabling condition. Multimodal physical therapy intervention may be helpful, yet studies of such approaches are not available and are the basis of this study.
Learn More >Depression, anxiety, and chronic pain are common comorbidities in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) and may substantially impact patient outcomes. We aimed to determine whether these comorbidities were associated with earlier TNF-inhibitor (TNFi) discontinuation.
Learn More >Females suffer higher rates of operative recurrence and chronic pain following groin hernia repair. Guidelines recommend minimally invasive (MIS) groin hernia repair as the preferred approach to reduce these adverse outcomes. It is unknown what proportion of females receive MIS hernia repair. Therefore, our goal was to investigate adoption of evidence-based practices in groin hernia repair using sex as a biological variable.
Learn More >To assess the effectiveness of pulsed electromagnetic field (PEMF) on pain and physical function in patients with low back pain.
Learn More >The purpose of this review is to synthesize recent literature investigating the use of regional anesthesia for minimally invasive surgery.
Learn More >The diagnostic criteria of new daily persistent headache (NDPH) have been revised since 2013. The current review focused on the progress of NDPH research over the last few years.
Learn More >Tapentadol is a centrally acting analgesic with a dual mechanism of action. It acts as an agonist at the µ receptor and inhibitor of noradrenaline reuptake. Clinical trials suggest similar analgesic efficacy of tapentadol, oxycodone, and morphine in acute and chronic pain. Given the limited information about the molecular actions of tapentadol at the µ receptor, we investigated the intrinsic efficacy of tapentadol and compared it with other opioids. β-chlornaltrexamine (β-CNA, 100 nM, 20 min) was used to deplete spare receptors in AtT20 cells stably transfected with human µ receptor wild-type (WT). Opioid-mediated changes in membrane potential were measured in real-time using a membrane potential-sensitive fluorescent dye. Using Black and Leff's operational model, intrinsic efficacy relative to DAMGO was calculated for each opioid. Tapentadol (0.05 ± 0.01) activated the GIRK channel with lesser intrinsic efficacy than morphine (0.17 ± 0.02) and oxycodone (0.16 ± 0.02). We further assessed the signaling of tapentadol in the common µ receptor variants (N40D and A6V) which are associated with altered receptor signaling. We found no difference in the response of tapentadol between these receptor variants.
Learn More >Migraine affects more than a billion people all over the world and requires critical employment of healthcare resources. Telemedicine could be a reasonable tool to manage people suffering from headaches, and it received a big push from the COVID-19 pandemic.
Learn More >Migraine is a ubiquitous neurologic disease that afflicts people of all ages. Its molecular pathogenesis involves peptides that promote intracranial vasodilation and modulate nociceptive transmission upon release from sensory afferents of cells in the trigeminal ganglion and parasympathetic efferents of cells in the sphenopalatine ganglion. Experimental data have confirmed that intravenous infusion of these vasoactive peptides induce migraine attacks in people with migraine, but it remains a point of scientific contention whether their site of action lies outside or within the central nervous system. In this context, it has been hypothesized that transient dysfunction of brain barriers before or during migraine attacks might facilitate the passage of migraine-inducing peptides into the central nervous system. Here, we review evidence suggestive of brain barrier dysfunction in migraine pathogenesis and conclude with lessons learned in order to provide directions for future research efforts.
Learn More >This is a summary of the published research from the 14 observational, longitudinal and big-data, epidemiological studies supported by the LIMBIC-CENC program from 2013-2021 examining the long-term effects of combat-related traumatic brain injury (TBI). Findings from these 43 primary and secondary analyses include: 1) unique fluid, advanced neuroimaging and electrophysiologic biomarkers associated with mild traumatic brain injury (mTBI), number of mTBIs and related dysfunction, 2) increases in a range of chronic difficulties, including neurosensory, sleep, pain, cognitive deficits, behavioral disorders, overall symptom burden, healthcare costs and service-connected disability, associated with mTBI, all-severity traumatic brain injury (TBI), blast exposure, and number of mTBIs, and 3) increases in the risk for suicide and neurodegeneration, including dementia and Parkinson's disease, associated with mTBI and all-severity TBI. Ongoing LIMBIC-CENC longitudinal and epidemiologic research will clarify, confirm and expand upon these findings.
Learn More >Despite the rapid advance in anti-cancer treatment in recent years, the treatment to cancer-related pain remains largely unchanged. One systemic review has shown that approximately 32% of patient with cancer-related pain were undertreated. While in patients responding to strong opioids, long-term use of opioids will lead to many undesired side effects such as constipation, tolerance, and addiction. The goals of this review are to re visit the current algorism of cancer pain management and bring attention to the emerging interventional pain management techniques.
Learn More >Young adults find themselves in an unstable phase of life with relationship breaks, falling structures and great challenges in life. Chronic pain makes it difficult to cope with this stage of life due to functional, emotional and social limitations. For this age group there are hardly any target group-specific treatment programs.
Learn More >Degeneration of the intervertebral disc is considered to be central in pain pathogenesis in patients suffering from chronic low back pain (LBP). In recent years, the injection of mesenchymal stromal cells (MSCs) into the disc to arrest or reverse the degenerative process has been proposed as an alternative therapy. The aim of the present study was to investigate the feasibility of using iron-labeled MSCs for intradiscal injection in patients with long-standing LBP.
Learn More >Alcoholic neuropathy emerges following the persistent alcohol imbibing, and triggers nerve damage through de-escalating the receptors situated in the central nervous system (CNS), which consecutively evolves into debilitating neuropathic state and further precipitates hyperalgesia, allodynia, dysesthesia, ataxia, numbness, immobility, and decline in certain body functions. Existing pharmacotherapy, such as anticonvulsants (gabapentin and topiramate), and antidepressant drugs (duloxetine, and venlafaxine) render short-lasting benefits; however, their continual use is not favoured nowadays because of their detrimental outcomes and habit-forming behaviour. Consequently, the research is being shifted towards exploring novel propitious targets which entirely assist in the cessation of the disease. This review discloses the multitudinous pathways implicated in the pathogenesis of alcoholic neuropathy, with special emphasis on purinergic and orexinergic receptors. Moreover, the review focuses on targeting purinergic (P2X, P2X, P2X, P2X, and P2Y), and orexinergic (OX1 and OX2) receptors associated with the evolution of alcoholic neuropathy, and to incentivize further investigation to attain novel propitious strategy in alcoholic neuropathy treatment. The mechanisms implicated in the progression of alcoholic neuropathy comprises malnourishment (B vitamins scarcity), direct pernicious outcomes of alcohol, increased oxidative-nitrosative stress, protein kinase C epsilon (PKCε), and extracellular signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) functioning, abnormalities in the axonal transport and cytoskeleton system, activation of nuclear factor-kappa B (NF-κB) and caspase pathway, stimulation of the sympathoadrenal and hypothalamo-pituitary-adrenal (HPA) axis, and microglial cells of spinal column. The purinergic receptor antagonists, orexins/orexinergic receptor antagonists eliminate/modulate hyperalgesia, allodynia, inflammatory pain, liberation of inflammatory mediators, NF-κB signalling pathway, ROS formation, nerve cell deterioration, and craving for alcohol consumption, thereby ceasing the evolution of alcoholic neuropathy. The authors focus to highlight the importance of this alternative strategy as a novel target in alcoholic neuropathy, and to incentivize researchers to scrutinize the possible benefits of purinergic and orexins/orexinergic receptors in the therapy of alcoholic neuropathy.
Learn More >Interoception is the sensation of the physiological state inside one's body. Growing evidence suggests that visual feedback of interoception improves body self-consciousness (BSC) and reduces pain perception among patients with chronic pain. However, whether the integration of exteroception and interoception influences pain processing in healthy individuals remains largely unknown. To examine this question, we combined the rubber hand illusion (RHI) paradigm with visualized interoception -flashing of an LED light on the rubber hand synchronously or asynchronously with participants' real-time heartbeats. Under these conditions, we tested pain thresholds and corresponding event-related potentials. The interoceptive visual feedback inhibited the P2 component of pain, and the RHI inhibited pre-stimulus alpha-band brain activity. BSC had no significant effect on the processing of pain. These findings demonstrate that interoceptive signals with visual feedback inhibit pain processing, and that this psychophysiological process is largely independent of reported self-consciousness, in healthy individuals.
Learn More >Sedentariness is a substantial risk for many chronic diseases. We aimed to investigate the correlation of sedentary behavior and its indicators with low back pain (LBP) among adults and children. Original articles published up to April 28, 2020, using PubMed, Embase, Web of Science and Scopus were evaluated. Odds ratio (OR, 95% CI) was considered the overall effect size for desired associations. We reviewed 49 English articles with analytical observational study design, of which, 27 studies with cross sectional/survey design were retained in the meta-analysis. Among adults, sedentary lifestyle was a considerable risk factor for LBP (OR=1.24, 1.02-1.5); prolonged sitting time (OR=1.42, 1.09-1.85) and driving time (OR=2.03, 1.22-3.36) were the significant risk factors. Sedentary behavior was associated with LBP in office workers (OR=1.23). Moreover, excess weight (OR=1.35, 1.14-1.59) and smoking (OR=1.28, 1.03-1.60) were associated with LBP. Among children, sedentary lifestyle was a remarkable risk factor for LBP (OR=1.41, 1.24- 1.60); prolonged TV watching (OR=1.23, 1.08-1.41) and computer/mobile using and console playing time (OR=1.63, 1.36-1.95) were significant risk factors for LBP. Consumption of coffee, however, has yield conflicting results to be considered as a risk factor. Moreover, the researches on the correlation between sedentariness and high-intensity LBP are scarce and inconclusive. Sedentary behavior, whether in work or leisure time, associates with a moderate increase in the risk of LBP in adults, children and adolescents.
Learn More >Chronic lower back pain is a crippling condition for the individual and a significant burden on society. It is notoriously challenging to manage despite access to invasive interventions. Understanding hypnosis as a powerful therapeutic adjunct to this condition allows holistic treatment of patients in distress.
Learn More >Sedation for pain medicine procedures provides a unique challenge for proceduralists. Many patients dealing with pain are on chronic opioids and require higher doses of sedation for adequate procedural comfort. Chronic pain patients have various comorbidities including depression, neuropsychiatric disorders, peripheral vascular disease, and renal impairment, among others [1]. These confounding variables make the overall treatment of their pain condition much more challenging.
Learn More >In migraineurs, coloured lenses were found to reduce the visual stress caused by an aversive pattern known to trigger migraines by 70%, but do such patterns also produce a low-level anxiety/fear response? Is this response lessened by colour? We sought to investigate this in a study comprising a broad screening component followed by a dot-probe experiment to elicit attentional biases (AB) to aversive patterns. Undergraduate psychology students completed headache and visual discomfort (VD) questionnaires ( = 358), thereby forming a subject pool from which 13 migraineurs with high visual discomfort and 13 no-headache controls with low visual discomfort, matched on age and sex, completed a dot-probe experiment. Paired stimuli were presented for 500 ms: aversive achromatic 3 cpd square wave gratings vs control, scrambled patterns. These conditions were repeated using the colour that was most comfortable for each participant. VD was greater in the more severe headache groups. On all measures, the migraineurs were more anxious than the controls, and a positive relationship was found between VD and trait anxiety. The 3 cpd gratings elicited an aversive AB in the migraine group which was somewhat reduced by the use of colour, and this was not seen in the controls. The results suggest a new role for colour in reducing visual stress via anxiety/fear reduction.
Learn More >To evaluate the effectiveness of telemedicine psychoeducational interventions (PIs) in adult patients on the clinical management of chronic non-oncological diseases compared with another therapeutic option or no treatment.
Learn More >Pulsed radiofrequency (PRF) of the occipital nerves has neuromodulative properties and is used for chronic pain management. However, its role in various types of chronic headaches has not been adequately investigated so far.
Learn More >Sumatriptan (ST) is a commonly prescribed drug for treating migraine. The efficiency of several routes of ST administration has been investigated. Recently, the intranasal route with different delivery systems has gained interest owing to its fast-acting and effectiveness. The present study is aimed at reviewing the available studies on novel delivery systems for intranasal ST administration. The oral route of ST administration is common but complicated with some problems. Gastroparesis in patients with migraine may reduce the absorption and effectiveness of ST upon oral use. Furthermore, the gastrointestinal (GI) system and hepatic metabolism can alter the pharmacokinetics and clinical effects of ST. The bioavailability of conventional nasal liquids is low due to the deposition of a large fraction of the delivered dose of a drug in the nasal cavity. Several delivery systems have been utilized in a wide range of preclinical and clinical studies to enhance the bioavailability of ST. The beneficial effects of the dry nasal powder of ST (AVP-825) have been proven in clinical studies. Moreover, other delivery systems based on microemulsions, microspheres, and nanoparticles have been introduced, and their higher bioavailability and efficacy were demonstrated in preclinical studies. Based on the extant findings, harnessing novel delivery systems can improve the bioavailability of ST and enhance its effectiveness against migraine attacks. However, further clinical studies are needed to approve the safety and efficacy of employing such systems in humans.
Learn More >To describe the prevalence of inflammatory and structural lesions using whole spine MRI in patients with psoriatic disease, and to assess their correlation with clinical features and with axial spondyloarthritis (axSpA) classification criteria.
Learn More >Spontaneous Trigeminal Neuralgia is a painful condition of the face which may require interventional treatment if medicines fail to control the pain. These include microvascular decompression (MVD) and GKNS. The former is moderately more effective but GKNS has become accepted both as an alternative to MVD or as an adjunct. Like all treatments of the condition, it is successful in a majority of patients but by no means all. Repeat treatments are possible. When Trigeminal Neuralgia is secondary to other conditions the response to GKNS is different. With AVMs, Dural Arteriovenous Fistulae and Epidermoids, the dose to treat the visible lesion usually cures the neuralgia. With meningiomas it is necessary to treat the neuralgia as a separate entity with a neuralgia dose focused on the nerve. GKNS does not improve the rare neuralgia associated with Vestibular Schwannomas. It works with Multiple Sclerosis but not as well as with the spontaneous illness. There is some evidence that GKNS can be useful with the rare Glossopharyngeal and Sphenopalatine Neuralgias.
Learn More >Since its adoption as a treatment for neuropathic pain in the 1960s, radiofrequency ablation (RFA) has continued to gain popularity for the management of various pain etiologies. Although RFA is considered to be a safe procedure, post-neurotomy neuritis (PNN), a neuropathic-type pain, is one of the most common side effects. Due to the increasing recognition of PNN, some providers have attempted to mitigate the risk of PNN by injecting local corticosteroids at the site of RFA following the procedure. Recent studies have generally concluded that corticosteroids do not protect against the development of PNN, however, they have been limited by their retrospective study designs and the low incidence of PNN.
Learn More >Pain management of patients with chronic pelvic pain syndrome (CPPS) is challenging, because pain is often refractory to conventional treatments. Botulinum toxin A (BTX-A) may represent a promising therapeutic strategy for these patients. The aim of this systematic review was to investigate the role of BTX-A in CPPS treatment.
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