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There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the μ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception.
Learn More >To identify and describe back pain (BP) trajectory groups and to compare indicators of health status, medication, and healthcare use by these groups.
Learn More >The benefits of opioid-based treatments to mitigate chronic pain can be hindered by the side effects of opioid-induced hyperalgesia (OIH) that can lead to higher consumption and risk of addiction. The present study advances the understanding of the molecular mechanisms associated with OIH by comparing mice presenting OIH symptoms in response to chronic morphine exposure (OIH treatment) relative to control mice (CON treatment). Using RNA-Seq profiles, gene networks were inferred in the trigeminal ganglia (TG), a central nervous system region associated with pain signaling, and in the nucleus accumbens (NAc), a region associated with reward dependency. The biological process of nucleic acid processing was over-represented among the 122 genes that exhibited a region-dependent treatment effect. Within the 187 genes that exhibited a region-independent treatment effect, circadian rhythm processes were enriched among the genes over-expressed in OIH relative to CON mice. This enrichment was supported by the differential expression of the period circadian clock 2 and 3 genes (Per2 and Per3). Transcriptional regulators in the PAR bZip family that are influenced by the circadian clock and that modulate neurotransmission associated with pain and drug addiction were also over-expressed in OIH relative to CON mice. Also notable was the under-expression in OIH relative to CON mice of the Toll-like receptor, nuclear factor-kappa beta, and interferon gamma genes and enrichment of the adaptive immune processes. The results from the present study offer insights to advance the effective use of opioids for pain management while minimizing hyperalgesia.
Learn More >Fibromyalgia-associated chronic pain occurring without organic causes exerts negative effects on patients' quality of life, thereby necessitating the development of superior drugs. Since non-organic pain in patients with fibromyalgia occurs without external stimuli, an endpoint measure that reflects patients' spontaneous pain should be implemented in preclinical research. The present study is the first to apply the rat grimace scale (RGS), a facial expression-dependent measure developed for quantifying spontaneous pain, to the rat with reserpine-induced myalgia, an animal model of fibromyalgia exhibiting non-organic pain. Animals were videotaped and still images of facial expressions were captured and scored in a blind fashion. The reserpine-induced myalgia rats exhibited a significant increase in the RGS score, which was sustained for 2 weeks or more after the induction of fibromyalgia-like state by reserpine injection. The period of RGS score elevation was similar to that of reduced paw withdrawal threshold (PWT) measured using the von Frey filament test, a conventional measure of evoked pain. The elevated RGS score and the decreased PWT were relieved by gabapentin (an αδ subunit ligand) and duloxetine (a serotonin and noradrenaline reuptake inhibitor), but not by diclofenac (a nonsteroidal anti-inflammatory drug), buprenorphine (a mu-opioid receptor agonist), or diazepam (a benzodiazepine). The present study suggests that facial expressions in reserpine-induced myalgia rats simulate non-organic pain occurring spontaneously in patients with fibromyalgia. This finding achieves a coordination of pain measures between the animal model and patients with fibromyalgia and would improve the translation of analgesic efficacies between them.
Learn More >Chronic itch is common in the elderly patient and may be caused by a variety of known dermatologic and non-dermatologic conditions and can have a significant effect on quality of life. Age-related changes in barrier function, immunosenescence, and neuronal changes and neuropathies are common predisposing factors to chronic itch in this age group. Certain primary dermatologic conditions are more common in the elderly and can cause chronic itch. Also, co-morbid diseases particularly of the renal, hepatobiliary, or hematologic systems, psychologic conditions, or medications may contribute to chronic itch in this population. Thus, medical workup for an elderly patient with chronic itch requires special attention to the patient's medical history, current health status, and medications. Topical treatments and emollients may be recommended for elderly patients, with consideration of specific adverse effects and alternatives. Systemic medications pose a higher risk of adverse effects and many are contraindicated in the elderly for this reason. In addition, management in the elderly may be complicated by differential pharmacokinetics of medications, the presence of co-morbid health conditions, cognitive disorders, physical limitations, and polypharmacy. New and emerging treatment modalities hold promise for use in the elderly due to these special considerations.
Learn More >Itch is a multidimensional experience involving various brain regions associated with sensory perception and emotion, as well as an urge to scratch employing the motor system. Scratch temporarily relieves itch sensation in healthy subjects. However, in patients with chronic itch, rather than inhibit, scratch may aggravate itch. Patients with chronic itch, such as those with atopic dermatitis, experience severe itch and a strong desire to scratch. This urge to scratch is the driving force underlying the formation of the itch scratch-cycle, an addictive and vicious cycle in chronic itch patients. This vicious itch-scratch behavior and various types of addiction (henceforth, including recreational drug use) were shown to share common sensory mechanisms. Abnormalities have been observed in central neural circuits, including the reward, motivation/drive, control, and learning/memory circuits, as well as other brain systems. Reward systems, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and striatum, are important for brain processing of both addiction and itch. In addition to reward, addicted individuals can experience severe disruptions in motor control, cognitive awareness, executive function, learning/memory and even emotional functions. Findings showing that addiction and itch share a common neurobiological foundation could have important mechanistic and therapeutic implications. Here we propose that similar neuroadaptations exist in addiction and chronic itch patients. This article is protected by copyright. All rights reserved.
Learn More >Loss of the keratin cytoskeleton results in upregulation of the pro-inflammatory cytokine Tslp via autocrine Areg-Egfr-Erk1/2 signaling. The Areg-Egfr axis represents a therapeutical target to moderate Tslp, inflammation and itch in EBS.
Learn More >Mast cells, eosinophils, and basophils are central effector immune cells in allergic skin inflammation including atopic dermatitis (AD). Recent studies revealed that the bidirectional interaction between these three immune cell types (mast cells, eosinophils, and basophils) and the nervous system is involved in the pathogenesis of neurogenic inflammation, pain, and pruritus. Emerging evidence shows that these cells are the main source of pruritogens such as histamine, neuropeptides, cytokines, which are potential new therapeutic targets for drug development in chronic pruritus. For instance, many Th2 cytokines including interleukin (IL)-4, 13, and 31 have been recognized as some of the most promising targets for the treatment of chronic pruritus in AD. In this review, we highlight the link between these three immune cell subsets and peripheral nerves, with emphasis on the development of chronic pruritus such as AD. We present cytokines and receptors of these three immune cells and peripheral nerves, and discuss the therapeutic potential of targeting these neuro-immunological processes. This article is protected by copyright. All rights reserved.
Learn More >Migraine with brainstem aura is a rare subtype of migraine with aura. Although this entity has been known for many years, its diagnosis and even its existence are still a matter of debate. Previous studies demonstrated that current diagnostic criteria for migraine with brainstem aura are too open and brainstem symptoms may originate within the cortex and not in the brainstem. The aims of the present study were to analyse whether aura from the brainstem exists, how prevalent such a core syndrome is, to analyse if current diagnostic criteria define such a core syndrome and, if necessary, to develop new diagnostic criteria that define only the core syndrome. We analysed all migraine with brainstem aura cases described in detail in the literature, clinical cases from the Danish Headache Center (DHC) and our large sample of telephone interviewed cases with migraine with aura. We selected the 20 most convincing cases from the literature and convincing cases from the DHC. Of 79 migraine with brainstem aura cases described in detail in the literature, 44 fulfilled the diagnostic criteria for migraine with brainstem aura of the International Classification of Headache Disorders, 3rd edition (ICHD-3). In the DHC after face-to-face interview, neurological examination and imaging, four migraine with brainstem aura of 293 cases with migraine with aura (1.37%) were found, corresponding to 0.04% of the general population. The 20 most convincing cases had symptoms that likely originated in the brainstem. Our telephone-interviewed cohort included 1781 subjects with a diagnosis of migraine with aura or probable migraine with aura. Of these, 228 fulfilled the diagnostic criteria for migraine with brainstem aura of the ICHD-3. Thus, using telephone interview diagnosis according to current diagnostic criteria results in too many cases of migraine with brainstem aura being diagnosed. Therefore, we developed stricter diagnostic criteria in an attempt to include only those rare cases that definitely have aura originating from the brainstem. Migraine with brainstem aura does exist, but it is very rare. Existing diagnostic criteria are too unspecific, but it was possible to develop tighter criteria that define a core syndrome probably caused by brainstem dysfunction.
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