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The effective prevention of postoperative cognitive dysfunction (POCD) needs to be explored, and the effect of preoperative pain on POCD remains unclear. We established a chronic pain model induced by chronic constriction injury (CCI) and models of acute pain and anxiety without pain in mice that were subsequently subjected to partial hepatectomy surgery. Morris water maze (MWM) tests were performed to evaluate the learning and memory abilities of the mice. ELISA was used to measure IL-1β, IL-6, and TNF-α in serum, and HPLC-MS was used to detect neurotransmitters in the prefrontal cortices and hippocampi of the mice. The results indicated that chronic pain induced by CCI might have significantly impaired the learning and memory abilities of mice, while acute pain and anxiety without pain only affected the memory abilities of mice. Perioperative acute pain increased the level of IL-1β in serum, and CCI might have increased the level of IL-6. CCI and acute pain increased dopamine (DA) levels in the cortex, similar to anxiety. Like anxiety, CCI increased 5-hydroxytryptamine (5-HT) levels in the prefrontal cortex and hippocampus. Acute pain led to a decrease in the acetylcholine (ACH) level in the hippocampus. Our results suggest that acute pain and CCI-induced chronic pain might aggravate postoperative cognitive dysfunction via neurotransmitters and by changing the levels of inflammatory factors such as IL-1β and IL-6.
Learn More >Nalfurafine, a moderately selective kappa opioid receptor (KOR) agonist, is used in Japan for treatment of itch without causing dysphoria or psychotomimesis. Here we characterized pharmacology of compound 42B, a 3-dehydroxy analog of nalfurafine and compared with that of nalfurafine. Nalfurafine and 42B acted as full KOR agonists and partial opioid receptor (MOR) agonists, but 42B showed much lower potency for both receptors and lower KOR/MOR selectivity, different from previous reports. Molecular modeling revealed that water-mediated hydrogen-bond formation between 3-OH of nalfurafine and KOR accounted for its higher KOR potency than 42B. The higher potency of both at KOR over MOR may be due to hydrogen-bond formation between non-conserved Y7.35 of KOR and their carbonyl groups. Both showed modest G protein signaling biases. In mice, like nalfurafine, 42B produced antinociceptive and anti-scratch effects and did not cause conditioned place aversion (CPA) in the effective dose ranges. Unlike nalfurafine, 42B caused motor incoordination and hypolocomotion. As both agonists showed G protein biases, yet produced different effects on locomotor activity and motor incoordination, the findings and those in the literature suggest caution in correlating in vitro biochemical data with in vivo behavior effects. The factors contributing to the disconnect, including pharmacodynamic and pharmacokinetic issues, are discussed. In addition, our results suggest that among the KOR-induced adverse behaviors, CPA can be separated from motor incoordination and hypolocomotion.
Learn More >The Mindfulness-Based Stress Reduction program is effective at improving chronic pain outcomes, but the time demand hinders participation. This preliminary study evaluated the feasibility, acceptability, and potential effects of providing an abbreviated mindfulness program for patients with chronic pain.
Learn More >Opioid use, misuse, and risky use contribute to a critically important and complex crisis in current healthcare. Consequences of long-term opioid use, including opioid induced hyperalgesia, physical dependence, and opioid use disorder, can be considered iatrogenic, or partially iatrogenic, in cases where therapeutic opioid exposures were contributory. Research investigation and presumptive clinical action are needed to attenuate the iatrogenic component of the opioid crisis; treatment of individuals already suffering from opioid use disorder will not prevent incident cases. This work will be challenged by a remarkably high degree of complexity involving myriad and highly variable factors along the continuum from initial opioid exposure to long-term opioid use. An organized view of this complex problem should accelerate the pace of innovation and facilitate clinical implementation of research findings. Herein, we propose a theoretical framework and modern nomenclature for characterizing therapeutic opioid exposure and the degree to which it contributes iatrogenically to adverse outcomes. In doing so, we separate the role of exposure from other factors contributing to long-term opioid use, clarify the relationship between opioid exposure and outcomes, emphasize that exposure source is an important consideration for health services research and practice in the areas of pain treatment and opioid prevention, and recommend terminology necessary to quantify therapeutic opioid exposure separately from nonmedical exposure.
Learn More >Knee osteoarthritis (OA) is a common source of pain in older adults. Although OA-induced pain can be relieved with analgesics and anti-inflammatory drugs, the current opioid epidemic is fostering the exploration of nonpharmacologic strategies for pain mitigation. Amongs these, transcranial direct current stimulation (tDCS) and mindfulness-based meditation (MBM) hold potential for pain-relief efficacy due to their neuromodulatory effects of the central nervous system, which is known to play a fundamental role in pain perception and processing.
Learn More >Mutations in the early growth response 2 gene (EGR2) cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc-finger (ZNF) DNA-binding domain.
Learn More >Although opioids have been used as treatment of neuropathic pain, opioids have abuse potential in humans. Since soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids plays a key role in the pain, sEH inhibitors would be promising new therapeutic drugs for neuropathic pain. In this study, we examined the effect of the sEH inhibitor TPPU on rewarding effects in mice using the conditioned place preference (CPP) paradigm.
Learn More >To explore the use of a multistate repeated, time-to-categorical event model describing the frequency, severity and duration of migraines.
Learn More >Innocuous mechanical stimuli, such as rubbing or stroking the skin, relieve itch through the activation of low-threshold mechanoreceptors (LTMRs). However, the mechanisms behind this inhibition remain unknown. We presently investigated whether stroking the skin reduces the responses of superficial dorsal horn neurons to pruritogens in male C57BL/6J mice. Single-unit recordings revealed that neuronal responses to chloroquine were enhanced during skin stroking, and this was followed by suppression of firing below baseline levels after the termination of stroking. Most of these neurons additionally responded to capsaicin. Stroking did not suppress neuronal responses to capsaicin, indicating state-dependent inhibition. Vesicular glutamate transporter 3 (VGLUT3)-lineage sensory nerves compose a subset of LTMRs. Stroking-related inhibition of neuronal responses to chloroquine was diminished by optogenetic inhibition of VGLUT3-lineage sensory nerves in male and female / mice. Conversely, in male and female mice, optogenetic stimulation of VGLUT3-lineage sensory nerves inhibited firing responses of spinal neurons to pruritogens after the termination of stimulation. This inhibition was nearly abolished by spinal delivery of the κ-opioid receptor antagonist nor-binaltorphimine dihydrochloride, but not the neuropeptide Y receptor Y1 antagonist BMS193885. Optogenetic stimulation of VGLUT3-lineage sensory nerves inhibited pruritogen-evoked scratching without affecting mechanical and thermal pain behaviors. Therefore, VGLUT3-lineage sensory nerves appear to mediate inhibition of itch by tactile stimuli.Rubbing or stroking the skin is known to relieve itch. We investigated the mechanisms behind touch-evoked inhibition of itch in mice. Stroking the skin reduced the activity of itch-responsive spinal neurons. Optogenetic inhibition of VGLUT3-lineage sensory nerves diminished stroking-evoked inhibition, and optogenetic stimulation of VGLUT3-lineage nerves inhibited pruritogen-evoked firing. Together, our results provide a mechanistic understanding of touch-evoked inhibition of itch.
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