Neurobiology of Pain最新文献

{"title":"Pain stickiness in pediatric complex regional pain syndrome: A role for the nucleus accumbens","authors":"Andrew M. Youssef ,&nbsp;Ke Peng ,&nbsp;Pearl Kijoo Kim ,&nbsp;Alyssa Lebel ,&nbsp;Navil F. Sethna ,&nbsp;Corey Kronman ,&nbsp;David Zurakowski ,&nbsp;David Borsook ,&nbsp;Laura E. Simons","doi":"10.1016/j.ynpai.2021.100062","DOIUrl":"10.1016/j.ynpai.2021.100062","url":null,"abstract":"<div><p>Some individuals with chronic pain experience improvement in their pain with treatment, whereas others do not. The neurobiological reason is unclear, but an understanding of brain structure and functional patterns may provide insights into pain’s responsivity to treatment. In this investigation, we used magnetic resonance imaging (MRI) techniques to determine grey matter density alterations on resting functional connectivity (RFC) strengths between pain responders and nonresponders in patients with complex regional pain syndrome. Brain metrics of pediatric patients at admission to an intensive pain rehabilitative treatment program were evaluated. Pain responders reported significant pain improvement at discharge and/or follow-up whereas nonresponders reported no improvements in pain, increases in pain, or emergence of new pain symptoms. The pain (responder/nonresponder) groups were compared with pain-free healthy controls to examine predictors of pain responder status via brain metrics. Our results show: (1) on admission, pain nonresponders had decreased grey matter density (GMD) within the nucleus accumbens (NAc) and reduced RFC strength between the NAc and the dorsolateral prefrontal cortex vs. responders; (2) Connectivity strength was positively correlated with change in pain intensity from admission to discharge; (3) Compared with pain-free controls, grey matter and RFC differences emerged only among pain nonresponders; and (4) Using a discriminative model, combining GMD and RFC strengths assessed at admission showed the highest prediction estimate (87%) on potential for pain improvement, warranting testing in a de novo sample. Taken together, these results support the idea that treatment responsiveness on pain is underpinned by concurrent brain structure and resting brain activity.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"9 ","pages":"Article 100062"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2021.100062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25489696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The naked mole-rat has a functional purinergic pain pathway despite having a non-functional peptidergic pain pathway","authors":"Brigitte M. Browe ,&nbsp;Abigail R. Olsen ,&nbsp;Cesar Ramirez ,&nbsp;Rebecca H. Rickman ,&nbsp;Ewan St. John Smith ,&nbsp;Thomas J. Park","doi":"10.1016/j.ynpai.2020.100047","DOIUrl":"10.1016/j.ynpai.2020.100047","url":null,"abstract":"<div><p>Naked mole-rats (<em>Heterocephalus glaber</em>) have adaptations within their pain pathway that are beneficial to survival in large colonies within poorly ventilated burrow systems, with lower O₂ and higher CO₂ ambient levels than ground-level environments. These adaptations ultimately lead to a partial disruption of the C-fiber pain pathway, which enables naked mole-rats to not feel pain from the acidosis associated with CO₂ accumulation. One hallmark of this disruption is that naked mole-rats do not express neuropeptides, such as Substance P and calcitonin gene-related peptide in their cutaneous C-fibers, effectively making the peptidergic pain pathway hypofunctional. One C-fiber pathway that remains unstudied in the naked mole-rat is the non-peptidergic, purinergic pathway, despite this being a key pathway for inflammatory pain. The current study aimed to establish the functionality of the purinergic pathway in naked mole-rats and the effectiveness of cannabinoids in attenuating pain through this pathway. Cannabinoids can manage chronic inflammatory pain in both humans and mouse models, and studies suggest a major downstream role for the purinergic receptor, P2X3, in this treatment. Here we used Ca²⁺-imaging of cultured dorsal root ganglion neurons and <em>in vivo</em> behavioral testing to demonstrate that the P2X3 pathway is functional in naked mole-rats. Additionally, formalin-induced inflammatory pain was reduced by the cannabinoid receptor agonist, WIN55 (inflammatory, but not acute phase) and the P2X3 receptor antagonist A-317491 (acute and inflammatory phases). This study establishes that the purinergic C-fiber pathway is present and functional in naked mole-rats and that cannabinoid-mediated analgesia occurs in this species.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"8 ","pages":"Article 100047"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2020.100047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37996122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The sad weekend: A perilous North American tradition","authors":"Stacie K. Totsch ,&nbsp;Keri M. Kemp ,&nbsp;Salvador A. Lopez ,&nbsp;Tammie L. Quinn ,&nbsp;Remy Y. Meir ,&nbsp;Barbara A. Gower ,&nbsp;Robert E. Sorge","doi":"10.1016/j.ynpai.2020.100053","DOIUrl":"10.1016/j.ynpai.2020.100053","url":null,"abstract":"<div><p>Obesity is a global concern and affects millions of Americans who consume poor-quality diets. Diets directly affect the gut microbiota, which can have subsequent effects on inflammation and contribute to other chronic states. Previously we have shown that a Standard American Diet (SAD) increased immune cell activation and prolonged recovery and that a beneficial diet could reduce these negative effects. Here, male and female mice were given access to regular chow (REG), SAD, our Anti-Inflammatory Diet (AID) or a combination of SAD and AID. This latter group was modeled on the commonplace dietary pattern of healthy eating during the week (AID: Monday-Friday) and relaxed eating patterns on the weekend (SAD: Saturday-Sunday). After 14 weeks of diet consumption and an inflammatory injury, we found that the SAD prolonged and the AID promoted recovery. However, recovery was significantly delayed in those mice consuming the AID-SAD, regardless of weekly healthy diet access. In addition, fecal samples taken during the study revealed dramatic differences in microbial community composition, relative abundance of abundant bacterial phyla and alpha diversity. These data confirm the impact of diet on gut microbiota and suggest a relation between abundance of specific bacterial taxa and susceptibility to prolonged recovery from injury.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"8 ","pages":"Article 100053"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2020.100053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38614769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Putative roles of SLC7A5 (LAT1) transporter in pain","authors":"Sascha R.A. Alles ,&nbsp;Kimberly Gomez ,&nbsp;Aubin Moutal ,&nbsp;Rajesh Khanna","doi":"10.1016/j.ynpai.2020.100050","DOIUrl":"10.1016/j.ynpai.2020.100050","url":null,"abstract":"<div><p>Large amino acid transporter 1 (LAT1), also known as SLC7A5, is an essential amino acid transporter that forms a heterodimeric complex with the glycoprotein cell-surface antigen heavy chain (4F2hc (CD98, SLC3A2)). Within nociceptive pathways, LAT1 is expressed in the dorsal root ganglia and spinal cord. Although LAT1 expression is upregulated following spinal cord injury, little is known about LAT1 in neuropathic pain. To date, only circumstantial evidence supports LAT1/4F2hc’s role in pain. Notably, LAT1′s expression and regulation link it to key cell types and pathways implicated in pain. Transcriptional regulation of LAT1 expression occurs via the Wnt/frizzled/β-catenin signal transduction pathway, which has been shown to be involved in chronic pain. The LAT1/4F2hc complex may also be involved in pain pathways related to T- and B-cells. LAT1′s expression induces activation of the mammalian target of rapamycin (mTOR) signaling axis, which is involved in inflammation and neuropathic pain. Similarly, hypoxia and cancer induce activation of hypoxia-inducible factor 2 alpha, promoting not only LAT1′s expression but also mTORC1′s activation. Perhaps the strongest evidence linking LAT1 to pain is its interactions with key voltage-gated ion channels connected to nociception, namely the voltage-gated potassium channels Kv1.1 and Kv1.2 and the voltage-gated sodium channel Nav1.7. Through functional regulation of these channels, LAT1 may play a role in governing the excitatory to inhibitory ratio which is altered in chronic neuropathic pain states. Remarkably, the most direct role for LAT1 in pain is to mediate the influx of gabapentin and pregabalin, two first-line neuropathic pain drugs, that indirectly inhibit high voltage-activated calcium channel auxiliary subunit α2δ-1. In this review, we discuss the expression, regulation, relevant signaling pathways, and protein interactions of LAT1 that may link it to the development and/or maintenance of pain. We hypothesize that LAT1 expressed in nociceptive pathways may be a viable new target in pain.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"8 ","pages":"Article 100050"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2020.100050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38196119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin protects from oxaliplatin induced peripheral neuropathy in rats","authors":"N.W. Martinez ,&nbsp;A. Sánchez ,&nbsp;P. Diaz ,&nbsp;R. Broekhuizen ,&nbsp;J. Godoy ,&nbsp;S. Mondaca ,&nbsp;A. Catenaccio ,&nbsp;P. Macanas ,&nbsp;B. Nervi ,&nbsp;M. Calvo ,&nbsp;F.A. Court","doi":"10.1016/j.ynpai.2020.100048","DOIUrl":"10.1016/j.ynpai.2020.100048","url":null,"abstract":"<div><p>Oxaliplatin is a commonly used drug to treat cancer, extending the rate of disease-free survival by 20% in colorectal cancer. However, oxaliplatin induces a disabling form of neuropathy resulting in more than 60% of patients having to reduce or discontinue oxaliplatin, negatively impacting their chance of survival. Oxaliplatin-induced neuropathies are accompanied by degeneration of sensory fibers in the epidermis and hyperexcitability of sensory neurons. These morphological and functional changes have been associated with sensory symptoms such as dysesthesia, paresthesia and mechanical and cold allodynia. Various strategies have been proposed to prevent or treat oxaliplatin-induced neuropathies without success. The anti-diabetic drug metformin has been recently shown to exert neuroprotection in other chemotherapy-induced neuropathies, so here we aimed to test if metformin can prevent the development of oxaliplatin-induced neuropathy in a rat model of this condition. Animals treated with oxaliplatin developed significant intraepidermal fiber degeneration, a mild gliosis in the spinal cord, and mechanical and cold hyperalgesia. The concomitant use of metformin prevented degeneration of intraepidermal fibers, gliosis, and the altered sensitivity. Our evidence further supports metformin as a new approach to prevent oxaliplatin-induced neuropathy with a potential important clinical impact.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"8 ","pages":"Article 100048"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2020.100048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38002747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic inflammatory pain alters alcohol-regulated frontocortical signaling and associations between alcohol drinking and thermal sensitivity","authors":"M. Adrienne McGinn ,&nbsp;Kimberly N. Edwards ,&nbsp;Scott Edwards","doi":"10.1016/j.ynpai.2020.100052","DOIUrl":"10.1016/j.ynpai.2020.100052","url":null,"abstract":"<div><p>Alcohol use disorder (AUD) is a chronic, relapsing psychiatric disorder that is characterized by the emergence of negative affective states. The transition from recreational, limited intake to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms for seeking alcohol. Past work has identified the emergence of significant hyperalgesia/allodynia in alcohol-dependent animals, which may serve as a key negative reinforcement mechanism. Chronic pain has been associated with enhanced extracellular signal-regulated kinase (ERK) activity in cortical and subcortical nociceptive areas. Additionally, both pain and AUD have been associated with increased activity of the glucocorticoid receptor (GR), a key mediator of stress responsiveness. The objectives of the current study were to first determine relationships between thermal nociceptive sensitivity and alcohol drinking in male Wistar rats. While inflammatory pain induced by complete Freund’s adjuvant (CFA) administration did not modify escalation of home cage drinking in animals over four weeks, the relationship between drinking levels and hyperalgesia symptoms reversed between acute (1 week) and chronic (3–4 week) periods post-CFA administration, suggesting that either the motivational or analgesic effects of alcohol may be altered over the time course of chronic pain. We next examined ERK and GR phosphorylation in pain-related brain areas (including the central amygdala and prefrontal cortex subregions) in animals experiencing acute withdrawal from binge alcohol administration (2 g/kg, 6 h withdrawal) and CFA administration (four weeks) to model the neurobiological consequences of binge alcohol exposure in the context of pain. We observed a significant interaction between alcohol and pain state, whereby alcohol withdrawal increased ERK phosphorylation across all four frontocortical areas examined, although this effect was absent in animals experiencing chronic inflammatory pain. Alcohol withdrawal also increased GR phosphorylation across all four frontocortical areas, but these changes were not altered by CFA. Interestingly, we observed significant inter-brain regional correlations in GR phosphorylation between the insula and other regions investigated only in animals exposed to both alcohol and CFA, suggesting coordinated activity in insula circuitry and glucocorticoid signaling in this context. The results of these studies provide a greater understanding of the neurobiology of AUD and will contribute to the development of effective treatment strategies for comorbid AUD and pain.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"8 ","pages":"Article 100052"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2020.100052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38446145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human sensory neurons derived from pluripotent stem cells for disease modelling and personalized medicine","authors":"Angelika Lampert ,&nbsp;David L. Bennett ,&nbsp;Lucy A. McDermott ,&nbsp;Anika Neureiter ,&nbsp;Esther Eberhardt ,&nbsp;Beate Winner ,&nbsp;Martin Zenke","doi":"10.1016/j.ynpai.2020.100055","DOIUrl":"10.1016/j.ynpai.2020.100055","url":null,"abstract":"<div><p>In this concise Mini-Review we will summarize ongoing developments of new techniques to study physiology and pathophysiology of the peripheral sensory nervous system in human stem cell derived models. We will focus on recent developments of reprogramming somatic cells into induced pluripotent stem cells, neural differentiation towards neuronal progenitors and human sensory neurons.</p><p>We will sum up the high potential of this new technique for disease modelling of human neuropathies with a focus on genetic pain syndromes, such as gain- and loss-of-function mutations in voltage-gated sodium channels. The stem cell derived human sensory neurons are used for drug testing and we will summarize their usefulness for individualized treatment identification in patients with neuropathic pain. The review will give an outlook on potential application of this technique as companion diagnostics and for personalized medicine.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"8 ","pages":"Article 100055"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2020.100055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38751963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral mechanisms of arthritic pain: A proposal to leverage large animals for in vitro studies","authors":"Sampurna Chakrabarti ,&nbsp;Minji Ai ,&nbsp;Frances M.D. Henson ,&nbsp;Ewan St. John Smith","doi":"10.1016/j.ynpai.2020.100051","DOIUrl":"https://doi.org/10.1016/j.ynpai.2020.100051","url":null,"abstract":"<div><p>Pain arising from musculoskeletal disorders such as arthritis is one of the leading causes of disability. Whereas the past 20-years has seen an increase in targeted therapies for rheumatoid arthritis (RA), other arthritis conditions, especially osteoarthritis, remain poorly treated. Although modulation of central pain pathways occurs in chronic arthritis, multiple lines of evidence indicate that peripherally driven pain is important in arthritic pain. To understand the peripheral mechanisms of arthritic pain, various <em>in vitro</em> and <em>in vivo</em> models have been developed, largely in rodents. Although rodent models provide numerous advantages for studying arthritis pathogenesis and treatment, the anatomy and biomechanics of rodent joints differ considerably to those of humans. By contrast, the anatomy and biomechanics of joints in larger animals, such as dogs, show greater similarity to human joints and thus studying them can provide novel insight for arthritis research. The purpose of this article is firstly to review models of arthritis and behavioral outcomes commonly used in large animals. Secondly, we review the existing <em>in vitro</em> models and assays used to study arthritic pain, primarily in rodents, and discuss the potential for adopting these strategies, as well as likely limitations, in large animals. We believe that exploring peripheral mechanisms of arthritic pain <em>in vitro</em> in large animals has the potential to reduce the veterinary burden of arthritis in commonly afflicted species like dogs, as well as to improve translatability of pain research into the clinic.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"8 ","pages":"Article 100051"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2020.100051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72103146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A role for the microbiota in complex regional pain syndrome?","authors":"Lara W. Crock ,&nbsp;Megan T. Baldridge","doi":"10.1016/j.ynpai.2020.100054","DOIUrl":"10.1016/j.ynpai.2020.100054","url":null,"abstract":"<div><p>Complex regional pain syndrome (CRPS) is a debilitating neuroinflammatory condition of unknown etiology. Symptoms include excruciating pain and trophic changes in the limbs as defined by the Budapest criteria. The severity and functional recovery of CRPS, unlike most pain conditions, is quantifiable using a variation of the Budapest criteria known as the CRPS severity score. Like many chronic pain conditions, CRPS is difficult to treat once pain has been present for more than 12 months. However, previous work has demonstrated that a subset of patients with new-onset CRPS (~50%) improve if treated within one year, while the rest have minimal to no symptom improvement. Unfortunately, this leads to permanent disability and often requires invasive and costly treatments such as spinal cord stimulation or long-term opioid therapy. Because the etiology is unknown, treatment is multimodal, and often supportive. Biomarkers that predict severity or resolution of symptoms would significantly change treatment but have not yet been identified. Interestingly, there are case reports of remission or resolution of CRPS symptoms with the use of antibiotics known to affect the gut flora. Mouse studies have demonstrated that modulation of the gut microbiome is anti-nociceptive in visceral, inflammatory and neuropathic pain models. We hypothesize that the variable clinical potential for recovery and response to therapy in CRPS may be secondary to or reflected in changes in the gut microbiota. We suggest that the microbiota may mediate or reflect clinical status via the metabolome, activation of the immune system and/or microglial activation. We hypothesize that the gut microbiome is a potential mediator in development and persistence of CRPS symptoms and propose that the clinical condition of CRPS could provide a unique opportunity to identify biomarkers of the microbiota and potential therapies to prevent pain chronification.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"8 ","pages":"Article 100054"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2020.100054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38361463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model","authors":"Daniela Baptista-de-Souza ,&nbsp;Diana Tavares-Ferreira ,&nbsp;Salim Megat ,&nbsp;Ishwarya Sankaranarayanan ,&nbsp;Stephanie Shiers ,&nbsp;Christopher M. Flores ,&nbsp;Sourav Ghosh ,&nbsp;Ricardo Luiz Nunes-de-Souza ,&nbsp;Azair Canto-de-Souza ,&nbsp;Theodore J. Price","doi":"10.1016/j.ynpai.2020.100049","DOIUrl":"10.1016/j.ynpai.2020.100049","url":null,"abstract":"<div><p>Though sex differences in chronic pain have been consistently described in the literature, their underlying neural mechanisms are poorly understood. Previous work in humans has demonstrated that men and women differentially invoke distinct brain regions and circuits in coping with subjective pain unpleasantness. The goal of the present work was to elucidate the molecular mechanisms in the basolateral nucleus of the amygdala (BLA) that modulate hyperalgesic priming, a pain plasticity model, in males and females. We used plantar incision as the first, priming stimulus and prostaglandin E₂ (PGE₂) as the second stimulus. We sought to assess whether hyperalgesic priming can be prevented or reversed by pharmacologically manipulating molecular targets in the BLA of male or female mice. We found that administering ZIP, a cell-permeable inhibitor of aPKC, into the BLA attenuated aspects of hyperalgesic priming induced by plantar incision in males and females. However, incision only upregulated PKCζ/PKMζ immunoreactivity in the BLA of male mice, and deficits in hyperalgesic priming were seen only when we restricted our analysis to male <em>Prkcz^−/−</em> mice. On the other hand, intra-BLA microinjections of pep2m, a peptide that interferes with the trafficking and function of GluA2-containing AMPA receptors, a downstream target of aPKC, reduced mechanical hypersensitivity after plantar incision and disrupted the development of hyperalgesic priming in both male and female mice. In addition, pep2m treatment reduced facial grimacing and restored aberrant behavioral responses in the sucrose splash test in male and female primed mice. Immunofluorescence results demonstrated upregulation of GluA2 expression in the BLA of male and female primed mice, consistent with pep2m findings. We conclude that, in a model of incision-induced hyperalgesic priming, PKCζ/PKMζ in the BLA is critical for the development of hyperalgesic priming in males, while GluA2 in the BLA is crucial for the expression of both reflexive and affective pain-related behaviors in both male and female mice in this model. Our findings add to a growing body of evidence of sex differences in molecular pain mechanisms in the brain.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"8 ","pages":"Article 100049"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2020.100049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38053014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}