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Estrogens are presumed to underlie, at least in part, the greater pain sensitivity and chronic pain prevalence that women experience compared to men. Although previous studies revealed populations of estrogen receptor-expressing neurons in primary afferents and in superficial dorsal horn neurons, there is little to no information as to the contribution of these neurons to the generation of acute and chronic pain. Here we molecularly characterized neurons in the mouse superficial spinal cord dorsal horn that express estrogen receptor α (ERα) and explored the behavioral consequences of their ablation. We found that spinal ERα-positive neurons are largely excitatory interneurons and many co-express substance P, a marker for a discrete subset of nociceptive, excitatory interneurons. After viral, caspase-mediated ablation of spinal ERα-expressing cells, we observed a significant decrease in the first phase of the formalin test, but in male mice only. Decreased nocifensive behavior was also observed in the second phase but only after combining results from male and female mice. ERα-expressing neuron-ablation also reduced pruritogen-induced scratching in both male and female mice. There were no ablation-related changes in mechanical or heat withdrawal thresholds or in capsaicin-induced nocifensive behavior. In chronic pain models, we found no change in Complete Freund's adjuvant-induced thermal or mechanical hypersensitivity, or in partial sciatic nerve injury-induced mechanical allodynia. We conclude that ERα labels a subpopulation of excitatory interneurons that are specifically involved in chemically-evoked persistent pain and pruritogen-induced itch. This article is protected by copyright. All rights reserved.
Spinal cord stimulation (SCS) is a known therapy for a variety of chronic pain conditions, but over time a number of patients proceed to explants.
Itch is a topic to which everyone can relate. The physiologic roles of itch are increasingly understood and appreciated. The pathophysiologic consequences of itch impact quality of life as much as pain. These dynamics have led to increasingly deep dives into the mechanisms that underlie and contribute to the sensation of itch. When the prior review on the Physiology of Itching was published in this journal, in 1941, itch was a black box of interest to a small number of neuroscientists and dermatologists. Itch is now appreciated as a complex and colorful Rubik's cube. Acute and chronic itch are being carefully scratched apart and reassembled by puzzle solvers across the biomedical spectrum. Mediators are being identified. Mechanisms blur boundaries of the circuitry that blend neuroscience and immunology. Measures involve psychophysics and behavioral psychology. The efforts associated with these approaches is positively impacting the care of itchy patients. There is now the potential to markedly alleviate itch, a condition that does not end life, but often ruins it. We review the itch field and provide a current understanding of the pathophysiology of itch. Itch is a disease, not only a symptom of disease.
The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the spinoparabrachial pathway underlying its functional role in nociceptive information processing remains elusive. Here, we report that the PBN directly relays nociceptive signals from the spinal cord to the intralaminar thalamic nuclei (ILN). We demonstrate that the spinal cord connects with the PBN in a bilateral manner and that the ipsilateral spinoparabrachial pathway is critical for nocifensive behavior. We identify Tacr1-expressing neurons as the major neuronal subtype in the PBN that receives direct spinal input and show that these neurons are critical for processing nociceptive information. Furthermore, PBN neurons receiving spinal input form functional monosynaptic excitatory connections with neurons in the ILN, but not the amygdala. Together, our results delineate the neural circuit underlying nocifensive behavior, providing crucial insight into the circuit mechanism underlying nociceptive information processing.
Cannabis is often used to manage pain among persons who suffer from chronic pain. Yet, despite much literature suggesting cannabis use problems are associated with mental health problems, little work has examined mechanisms of this relationship among a chronic pain population. Chronic pain is also associated with emotion dysregulation. Individuals with chronic pain who experience cannabis use problems may have less capacity to regulate negative emotions, which could relate to greater anxiety, depression, and suicidal ideation. Thus, the current study explored whether emotion dysregulation explained, in part, the relation between cannabis use problems and anxiety, depression, and suicidal ideation among adults with chronic pain. Participants were 431 opioid-using adults with current moderate to severe chronic pain, 176 were current cannabis users, of which 30.20% reported cannabis use problems. Results indicated a significant indirect relationship between cannabis use problems and anxiety [95% CI (.03, .05)], depression [95% CI (.03, .06)], and suicidal ideation [95% CI (.01, .01)] via emotion dysregulation. Tests of specificity suggested potential for a bi-directional effect for suicidal ideation (.001). Initial findings suggest that emotion dysregulation may be an important mechanism in the relationship between cannabis use problems and mental health among adults with chronic pain.
Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W293 (Ballesteros-Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W318, Y326, and Y336 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR-ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.
Pain and depression are common in the population and co-morbid with each other. Both are predictive of one another and are also associated with cognitive function; people who are in greater pain and more depressed respectively perform less well on tests of cognitive function. It has been argued that pain might cause deterioration in cognitive function, whereas better cognitive function earlier in life might be a protective factor against the emergence of disease. When looking at the dynamic relationship between these in chronic diseases, studying samples that already have advanced disease progression often confounds this relationship.
Despite being a life-restricting condition, chronic pain remains poorly treated. A better understanding of the underlying mechanisms of chronic pain and thence development of innovative targets is therefore essential. Recently we have started to elucidate the importance of the role of microRNAs (miRs) in preclinical chronic pain. miRs are small, non-coding RNAs that regulate genes including those involved in nociceptive signalling. MiRs can exert their effects both intracellularly and extracellularly, the latter of which requires that they are released either as naked species or packaged in exosomes. Here we discuss changes in miR expression that occur in the dorsal root ganglia in murine models of chronic pain. We consider the downstream targets of changes in miR expression, including voltage-gated ion channels, as well as discuss extracellular consequences such as changes in macrophage phenotype that constitute of means by which neuron-immune cell crosstalk occurs. Such miR-mediated intracellular communication could provide a novel target for the treatment of chronic pain, which would be most effective if tailored to the specific cause of pain. Indeed, we conclude by reviewing evidence for the involvement of miRs in clinical cases of chronic pain, supporting the notion that tailored, miR-targeted therapies could prove to be an effective new strategy for the treatment of chronic pain clinically.
Our aim was to assess gender differences in variables associated with the emotional and physical burdens of tension-type headache (TTH). Participants with TTH diagnosed according to the ICHD-III were recruited from three university-based hospitals (in Spain, Italy, Denmark) between January 2015 and June 2017. The physical/emotional headache burden was assessed with the Headache Disability Inventory (HDI-P/HDI-E, respectively). Headache features were collected with a four-week diary. Sleep quality was assessed with Pittsburgh Sleep Quality Index. The Hospital Anxiety and Depression Scale evaluated anxiety and depressive symptom levels. Trait and state anxiety levels were evaluated with the State-Trait Anxiety Inventory. Two hundred and twelve (28% men) participants (aged 41-48 years old) participated. Multiple regression models revealed that sleep quality explained 36.7% of the variance of HDI-E and 31.1% of the variance of HDI-P in men, whereas headache intensity, depressive levels, and younger age explained 37.5% of the variance of HDI-E and 32.8% of the variance of HDI-P in women (all < .001). This study observed gender differences in variables associated with headache burden in TTH. Management of men with TTH should focus on interventions targeting sleep quality, whereas the management of women with TTH should combine psychological approaches and interventions targeting pain mechanisms.