Neurobiology of Pain最新文献

Chronic pain is a common and often debilitating problem that affects 100 million Americans. A better understanding of pain’s molecular mechanisms is necessary for developing safe and effective therapeutics. Microglial activation has been implicated as a mediator of chronic pain in numerous preclinical studies; unfortunately, translational efforts using known glial modulators have largely failed, perhaps at least in part due to poor specificity of the compounds pursued, or an incomplete understanding of microglial reactivity. In order to achieve a more granular understanding of the role of microglia in chronic pain as a means of optimizing translational efforts, we utilized a clinically-informed mouse model of complex regional pain syndrome (CRPS), and monitored microglial activation throughout pain progression. We discovered that while both males and females exhibit spinal cord microglial activation as evidenced by increases in Iba1, activation is attenuated and delayed in females. We further evaluated the expression of the newly identified microglia-specific marker, TMEM119, and identified two distinct populations in the spinal cord parenchyma after peripheral injury: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells, which are comprised of Ly6G + neutrophils and Ly6G- macrophages/monocytes. Neurons are sensitized by inflammatory mediators released in the CNS after injury; however, the cellular source of these cytokines remains somewhat unclear. Using multiplex in situ hybridization in combination with immunohistochemistry, we demonstrate that spinal cord TMEM119+ microglia are the cellular source of cytokines IL6 and IL1β after peripheral injury. Taken together, these data have important implications for translational studies: 1) microglia remain a viable analgesic target for males and females, so long as duration after injury is considered; 2) the analgesic properties of microglial modulators are likely at least in part related to their suppression of microglial-released cytokines, and 3) a limited number of neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury but have unknown impact on pain persistence or resolution. Further studies to uncover glial-targeted therapeutic interventions will need to consider sex, timing after injury, and the exact target population of interest to have the specificity necessary for translation.

As our definition of pain evolves, the factors implicit in defining and predicting pain status grow. These factors each have unique data characteristics and their outcomes each have unique target attributes. The clinical characterization of pain does not, as defined in the most recent IASP definition, require any tissue pathology, suggesting that the experience of pain can be uniquely psychological in nature. Predicting a persons pain status may be optimized through integration of multiple independent observations; however, how they are integrated has direct relevance towards predicting chronic pain development, clinical application, and research investigation. The current challenge is to find clinically-mindful ways of integrating clinical pain rating scales with neuroimaging of the peripheral and central nervous system with the biopsychocial environment and improving our capacity for diagnostic flexibility and knowledge translation through data modeling. This commentary addresses how our current knowledge of pain phenotypes and risk factors interacts with statistical models and how we can proceed forward in a clinically responsible way.

Migraine stands as one of the most disabling neurological conditions worldwide. It is a disorder of great challenge to study given its heterogeneous representation, cyclic nature, and complexity of neural networks involved. Despite this, clinical and preclinical research has greatly benefitted from the use of the nitric oxide donor, nitroglycerin (NTG), to model this disorder, dissect underlying mechanisms, and to facilitate the development and screening of effective therapeutics. NTG is capable of triggering a migraine attack, only in migraineurs or patients with a history of migraine and inducing migraine-like phenotypes in rodent models. It is however unclear to what extent NTG and NO, as its breakdown product, is a determinant factor in the underlying pathophysiology of migraine, and importantly, whether it really does facilitate the translation from the bench to the bedside, and vice-versa. This review provides an insight into the evidence supporting the strengths of this model, as well as its limitations, and shines a light into the possible role of NO-related mechanisms in altered molecular signalling pathways.

• This review summarizes major findings and recent advances in magnetic resonance spectroscopy (MRS) of migraine. A multi database search of PubMed, EMBASE, and Web of Science was performed with variations of magnetic resonance spectroscopy and headache until 20th September 2021. The search generated 2897 studies, 676 which were duplicates and 1836 were not related to headache. Of the remaining 385 studies examined, further exclusions for not migraine (n = 114), and not MRS of human brain (n = 128), and non-original contributions (n = 51) or conferences (n = 24) or case studies (n = 11) or non-English (n = 3), were applied. The manuscripts of all resulting reports were reviewed for their possible inclusion in this manuscript (n = 54). The reference lists of all included reports were carefully reviewed and articles relevant to this review were added (n = 2).

Background

Management of pain post-surgery is crucial for tissue healing in both veterinary and human medicine. Overuse of some analgesics such as opioids may lead to addictions and worsen pain syndromes (opioid-induced hyperalgesia), while underuse of it may affect the welfare of the patient. Therefore, the importance of using surgery models in laboratory animals is increasing, with the goal of improving our understanding of pain neurobiology and developing safer analgesics.

Methods

We compared the widely used plantar incision model with the laparotomy surgery model and measured pain-related behaviors using both spontaneous and evoked responses in female and male C57BL/6J mice. Additionally, we assessed conditioned place preference (CPP) and sucrose preference tests to measure pain-induced motivation for the analgesic ketoprofen and anhedonia-like behavior.

Results

Laparotomized mice showed increased abdominal sensitivity while paw-incised mice showed increased paw thermal and mechanical sensitivity up to seven days post-surgery. Laparotomy surgery reduced all spontaneous behaviors in our study however this effect dissipated by 24 h post-laparotomy. On the other hand, paw incision only reduced the percentage of cage hanging in a sex-dependent manner at 6 h post-incision. We also showed that both surgery models increased conditioned place preference for ketoprofen while preference for sucrose was only reduced at 24 h post-laparotomy. Laporatomy, but not paw incision, induced a decrease in body weight at 24 h post-surgery. Neither surgery model affected fluid intake.

Conclusion

Our results indicate that post-surgery hypersensitivity and behavioral deficits may differ by the incision site. Furthermore, factors associated with the surgery including length of the incision, duration of the anesthesia, and the layers that received stitches may affect subsequent spontaneous behaviors. These findings may help to improve drug development or the choice of the effective analgesic, depending on the surgery type.

Chronic migraine is one of the most devastating headache disorders. The estimated prevalence is 1.4–2.2% in the population. The factors which may predispose to the process of migraine progression include high frequency of migraine attacks, medication overuse, comorbid pain syndromes, and obesity. Several studies showed that chronic migraine results in the substantial anatomical and physiological changes in the brain. Despite no clear explanation regarding the pathophysiologic process leading to the progression, certain features such as increased sensory sensitivity, cutaneous allodynia, impaired habituation, identify the neuronal hyperexcitability as the plausible mechanism. In this review, we describe two main mechanisms which can lead to this hyperexcitability. The first is persistent sensitization caused by repetitive and prolonged trigeminal nociceptive activation. This process results in changes in several brain networks related to both pain and non-pain behaviours. The second mechanism is the decrease in endogenous brainstem inhibitory control, hence increasing the excitability of neurons in the trigeminal noceptive system and cerebral cortex. The combination of increased pain matrix connectivity, including hypothalamic hyperactivity and a weak serotonergic system, may contribute to migraine chronification.

Migraine is one of the most common pain disorders and causes disability in millions of people every year. Delta opioid receptors (DOR) have been identified as a novel therapeutic target for migraine and other headache disorders. DORs are present in both peripheral and central regions and it is unclear which receptor populations regulate migraine-associated effects. The aim of this study was to determine if DOR expressed in peripheral nociceptors regulates headache associated endpoints and the effect of delta agonists within these mouse models. We used a conditional knockout, in which DOR was selectively deleted from Nav1.8 expressing cells. Nav1.8-DOR mice and loxP control littermates were tested in models of chronic migraine-associated allodynia, opioid-induced hyperalgesia, migraine-associated negative affect, and aura. Nav1.8-DOR and loxP mice had comparable effect sizes in all of these models. The anti-allodynic effect of the DOR agonist, SNC80, was slightly diminished in the nitroglycerin model of migraine. Intriguingly, in the OIH model the peripheral effects of SNC80 were completely lost in Nav1.8-DOR mice while the cephalic effects remained intact. Regardless of genotype, SNC80 continued to inhibit conditioned place aversion associated with nitroglycerin and decreased cortical spreading depression events associated with migraine aura. These results suggest that DOR in Nav1.8-expressing nociceptors do not critically regulate the anti-migraine effects of delta agonist; and that brain-penetrant delta agonists would be a more effective drug development strategy.

Low-dose interleukin-2 (LD-IL-2) treatment has been shown to effectively reverse chronic migraine-related behaviors and the sensitization of trigeminal ganglion (TG) neurons through expansion and activation of peripheral regulatory T cells (Tregs) in mice. In this study, we investigated the molecular mechanisms underlying the effects of LD-IL-2 and Treg cells. LD-IL-2 treatment increases the production of cytokines interleukin-10 (IL-10) and transforming growth factor beta-1 (TGFβ1) in T cells, especially Treg cells, suggesting that they may mediate the therapeutic effect of LD-IL-2. Indeed, neutralizing antibodies against either IL-10 or TGFβ completely blocked the effects of LD-IL-2 on the facial mechanical hypersensitivity as well as the sensitization of TG neurons resulting from repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration in mice, indicating that LD-IL-2 and Treg cells engage both peripheral IL-10 and TGFβ signaling pathways to reverse chronic-migraine related sensitizations. In an in vitro assay, incubation of TG culture with exogenous IL-10 or TGFβ1 fully reversed NTG-induced sensitization of TG neurons, suggesting that the IL-10 and TGFβ1 signaling in TG neurons contribute to LD-IL-2′s therapeutic effects. Collectively, these results not only elucidate the molecular mechanisms through which LD-IL-2 and Treg cells reverse chronic-migraine related sensitizations, but also suggest that the IL-10 and TGFβ1 signaling pathways in TG neurons are potential targets for chronic migraine therapy.

Despite recent progress regarding inexpensive medical approaches, many individuals suffer from moderate to severe pain globally. The discovery and advent of exosomes, as biological nano-sized vesicles, has revolutionized current knowledge about underlying mechanisms associated with several pathological conditions. Indeed, these particles are touted as biological bio-shuttles with the potential to carry specific signaling biomolecules to cells in proximity and remote sites, maintaining cell-to-cell communication in a paracrine manner. A piece of evidence points to an intricate relationship between exosome biogenesis and autophagy signaling pathways at different molecular levels. A close collaboration of autophagic response with exosome release can affect the body’s hemostasis and physiology of different cell types. This review is a preliminary attempt to highlight the possible interface of autophagy flux and exosome biogenesis on pain management with a special focus on neuropathic pain. It is thought that this review article will help us to understand the interplay of autophagic response and exosome biogenesis in the management of pain under pathological conditions. The application of therapies targeting autophagy pathway and exosome abscission can be an alternative strategy in the regulation of pain.

Calcitonin gene-related peptide (CGRP) is considered a major player in migraine pathophysiology. However, the location and mechanisms of CGRP actions in migraine are not clearly elucidated. One important question yet to be answered is: Does central CGRP signaling play a role in migraine? One candidate site is the cerebellum, which serves as a sensory and motor integration center and is activated in migraine patients. The cerebellum has the most CGRP binding sites in the central nervous system and a deep cerebellar nucleus, the medial nucleus (MN), expresses CGRP (MN^CGRP). A previous study demonstrated that CGRP delivery into the cerebellum induced migraine-like behaviors. We hypothesized that stimulation of MN^CGRP neurons might induce migraine-like behaviors. To test the hypothesis, we used an optogenetic strategy using Calca^Cre/+ mice to drive Cre-dependent expression of channelrhodopsin-2 selectively in CGRP neurons in the cerebellar MN. A battery of behavioral tests was done to assess preclinical behaviors that are surrogates of migraine symptoms, including light aversion, cutaneous allodynia, and spontaneous pain when MN^CGRP neurons were optically stimulated. Motor functions were also assessed. Optical stimulation of MN^CGRP neurons decreased the time spent in the light, which was coupled to increased time spent resting in the dark, but not the light. These changes were only significant in female mice. Plantar tactile sensitivity was increased in the ipsilateral paws of both sexes, but contralateral paw data were less clear. There was no significant increase in anxiety-like behavior, spontaneous pain (squint), or changes in gait. These discoveries reveal that MN^CGRP neurons may contribute to migraine-like sensory hypersensitivity to light and touch.