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Cognitive impairment is one of the most common complications associated with chronic pain. Almost 20% of chronic pain patients suffer from cognitive impairment, which may substantially influence their quality of life. Levels of major excitatory neurotransmitters in the central nervous system, and alterations in the glutamatergic system may influence cognitive function and the pain sensory pathway. In the present study, we adopted the spare nerve injury model to establish the progress of chronic pain and investigated the mechanism underlying the cognitive aspect related to it. At behavioral level, using the novel-object recognition test, mechanical hypersensitivity was observed in peripheral nerve injured rats as they exhibited recognition deficits. We showed a dramatic decrease in hippocampal glutamate concentration using nuclear magnetic resonance and reduced glutamatergic synaptic transmission using whole-cell recordings. These were associated with deficient hippocampal long-term potentiation induced by high-frequency stimulation of the Schaffer collateral afferent. Ultra-high performance liquid chromatography revealed lower levels of D-serine in the hippocampus of SNI rats and that D-serine treatment could restore synaptic plasticity and cognitive dysfunction. The reduction of excitatory synapses was also increased by administering D-serine. These findings suggest that chronic pain has a critical effect on synaptic plasticity linked to cognitive function and may built up a new target for the development of cognitive impairment under chronic pain conditions.
Learn More >In an oversaturated market of publicly available mobile apps for psychosocial self-care and stress management, health care providers, patients, and consumers interested in mental health-related apps may wonder which, if any, are efficacious. Readily available metrics for consumers include user popularity and media buzz rather than scientific evidence.
Learn More >We aimed to assess the association between migraine headache and incident dementia.
Learn More >Implicit motor imagery performance is altered in a variety of chronic pain conditions, but it is not known whether this is the case in shoulder pain.
Learn More >Chronic musculoskeletal pain has a vast global prevalence and economic burden. Conservative therapies are universally recommended but require patient engagement and self-management to be effective.
Learn More >Even though endothelial dysfunction is known to play a role in migraine pathophysiology, studies regarding levels of endothelial biomarkers in migraine have controversial results. Our aim was to evaluate the role of pentraxin 3 (PTX3) and soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) as potential biomarkers of endothelial dysfunction in chronic migraine (CM). We performed a case-control study including 102 CM patients and 28 control subjects and measured serum levels of markers of endothelial dysfunction (PTX3 and sTWEAK) and inflammation [high-sensitivity C-reactive protein (hs-CRP)] as well as brachial artery flow-mediated dilation (FMD) during interictal periods. Interictal serum levels of PTX3 and sTWEAK were higher in CM patients than in controls (1350.6 ± 54.8 versus 476.1 ± 49.4 pg/mL, < 0.001 and 255.7 ± 21.1 versus 26.4 ± 2.6 pg/mL, < 0.0001; respectively). FMD was diminished in CM patients compared to controls (9.6 ± 0.6 versus 15.2 ± 0.9%, < 0.001). Both PTX3 and sTWEAK were negatively correlated with FMD (r = -0.508, < 0.001 and r = -0.188, = 0.033; respectively). After adjustment of confounders, PTX3 remained significantly correlated to FMD (r = -0.250, = 0.013). Diagnosis of CM was 68.4 times more likely in an individual with levels of PTX3 ≥ 832.5 pg/mL, suggesting that PTX3 could be a novel biomarker of endothelial dysfunction in CM.
Learn More >No large-cohort studies that examine racial effects on placebo hypoalgesic effects exist. To fill this void, we studied placebo effects in healthy and chronic pain participants self-identified as either African-American/Black (AA/Black) or White. We enrolled 372 study participants, 186 with a diagnosis of temporomandibular disorder (TMD) and 186 race, sex, and age matched healthy participants to participate in a placebo experiment. Using a well-established paradigm of classical conditioning with verbal suggestions, each individual pain sensitivity was measured to calibrate the temperatures for high- and low-pain stimuli in the conditioning protocol. These two temperatures were then paired with a red and green screen, respectively, and participants were told that the analgesic intervention would activate during the green screens to reduce pain. Participants then rated the painfulness of each stimulus on a Visual Analog Scale ranging from 0-100. Racial influences were tested on conditioning strength, reinforced expectations and placebo hypoalgesia. We found that White participants reported greater conditioning effects, reinforced relief expectations, and placebo effects when compared to their AA/Black counterparts. Racial effects on placebo were observed in TMD although negligible, short-lasting, and mediated by conditioning strength. Secondary analyses on the effect of experimenter-participant race and sex concordance indicated that same experimenter-participant race induced greater placebo hypoalgesia in TMDs while different sex induced greater placebo hypoalgesia in healthy participants. This is the largest study to analyze racial effects on placebo hypoalgesia and has implications for both clinical research and treatment outcomes.
Learn More >We investigated the contribution of nucleus locus ceruleus (LC) to the development of pain-associated affective behavior. Mice of both sexes were subjected to sciatic nerve cuffing, a model of peripheral nerve injury, and monitored for 45 days. While the thermal and mechanical thresholds were equally decreased in both males and females, only the male mice developed anxiodepressive-like behavior, which was complemented by suppressed hippocampal neurogenesis. Furthermore, the LC activity was lower in males when compared to females subjected to sciatic cuffing. Next, we used a chemogenetic approach to modulate the activity of LC projections to the dentate gyrus of the hippocampus in females without cuffs and in males with sciatic cuffs. Sustained inhibition of the LC projections to the dentate gyrus for 15 days induced anxiodepressive-like behavior and reduced the hippocampal neurogenesis in females. Activation of the LC projections to the dentate gyrus for 15 days prevented the development of anxiodepressive-like behavior and increased the hippocampal neurogenesis in males with cuffs. In sum, we demonstrated that the LC projections to the hippocampus link the sensory to the affective component of neuropathic injury and that the female mice are able to dissociate the nociception from affect by maintaining robust LC activity.
Learn More >Toll-like receptor 7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons.
Toll like receptor 7 (TLR7) is expressed in neurons of the dorsal root ganglion (DRG), but whether it contributes to neuropathic pain is elusive. We found that peripheral nerve injury caused by ligation of the fourth lumbar (L) spinal nerve (SNL) or chronic constriction injury of sciatic nerve led to a significant increase in the expression of TLR7 at mRNA and/or protein levels in mouse injured DRG. Blocking this increase through microinjection of the adeno-associated virus (AAV) 5 expressing TLR7 shRNA into the ipsilateral L DRG alleviated the SNL-induced mechanical, thermal and cold pain hypersensitivities in both male and female mice. This microinjection also attenuated the SNL-induced increases in the levels of phosphorylated extracellular signal-regulated kinase ½ (p-ERK1/2) and glial fibrillary acidic protein (GFAP) in L dorsal horn on the ipsilateral side during both development and maintenance periods. Conversely, mimicking this increase through microinjection of AAV5 expressing full-length TLR7 into unilateral L DRGs led to elevations in the amounts of p-ERK1/2 and GFAP in the dorsal horn, augmented responses to mechanical, thermal and cold stimuli, and induced the spontaneous pain on the ipsilateral side in the absence of SNL. Mechanistically, the increased TLR7 activated the NF-κB signaling pathway through promoting the translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from the injured DRG neurons. Our findings suggest that DRG TLR7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons. TLR7 may be a potential target for therapeutic treatment of this disorder.
Learn More >Electrophysiological approaches provide powerful tools to further our understanding of how different opioids affect signaling through opioid receptors; how opioid receptors modulate circuitry involved in processes such as pain, respiration, addiction and feeding; and how receptor signaling and circuits are altered by physiological challenges such as injury, stress and chronic opioid treatment. The use of genetic manipulations to alter or remove mu opioid receptors (MORs) with anatomical and cell-type specificity and the ability to activate or inhibit specific circuits through opto- or chemo-genetic approaches are being used in combination of electrophysiological, pharmacological, and systems-level physiology experiments to expand our understanding of the beneficial and mal-adaptive roles of opioids and opioid receptor signaling. New approaches for studying endogenous opioid peptide signaling and release and the dynamics of these systems in response to chronic opioid use, pain and stress will add another layer to our understanding of the intricacies of opioid modulation of brain circuits. This understanding will lead to new targets or approaches for drug development or treatment regimens that may affect both acute and long-term effects of manipulating the activity of circuits involved in opioid-mediated physiology and behaviors. This review will discuss recent advancements in our understanding of the role of phosphorylation in regulating MOR signaling as well as our understanding of circuits and signaling pathways mediating physiological behaviors such as respiratory control and discuss how electrophysiological tools combined with new technologies have and will continue to advance the field of opioid research. SIGNIFICANCE STATEMENT: This review discusses recent advancements in our understanding of mu opioid receptor function and regulation and the role of electrophysiological approaches combined with new technologies in pushing the field of opioid research forward. This covers regulation of MOR at the receptor level, adaptations induced by chronic opioid treatment, sites of action of MOR modulation of specific brain circuits and the role of the endogenous opioid system in driving physiology and behavior through modulation of these brain circuits.
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