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Tonic pain, a chief clinical problem, is difficult to study in rodent models that measure threshold changes of evoked reactions to acutely applied stimuli. These authors used conditioned place preference to assess tonic pain in rats and measure the efficacy of agents that relieve it. Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.

Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.

Recent changes in cannabis accessibility have provided adjunct therapies for patients across numerous disease states and highlights the urgency in understanding how cannabinoids and the endocannabinoid (EC) system interact with other physiological structures. The EC system plays a critical and modulatory role in respiratory homeostasis and pulmonary functionality. Respiratory control begins in the brainstem without peripheral input, and coordinates the preBötzinger complex, a component of the ventral respiratory group that interacts with the dorsal respiratory group to synchronize burstlet activity and drive inspiration. An additional rhythm generator: the retrotrapezoid nucleus/parafacial respiratory group drives active expiration during conditions of exercise or high CO 2 . Combined with the feedback information from the periphery: through chemo- and baroreceptors including the carotid bodies, the cranial nerves, stretch of the diaphragm and intercostal muscles, lung tissue, and immune cells, and the cranial nerves, our respiratory system can fine tune motor outputs that ensure we have the oxygen necessary to survive and can expel the CO 2 waste we produce, and every aspect of this process can be influenced by the EC system. The expansion in cannabis access and potential therapeutic benefits, it is essential that investigations continue to uncover the underpinnings and mechanistic workings of the EC system. It is imperative to understand the impact cannabis, and exogenous cannabinoids have on these physiological systems, and how some of these compounds can mitigate respiratory depression when combined with opioids or other medicinal therapies. This review highlights the respiratory system from the perspective of central versus peripheral respiratory functionality and how these behaviors can be influenced by the EC system. This review will summarize the literature available on organic and synthetic cannabinoids in breathing and how that has shaped our understanding of the role of the EC system in respiratory homeostasis. Finally, we look at some potential future therapeutic applications the EC system has to offer for the treatment of respiratory diseases and a possible role in expanding the safety profile of opioid therapies while preventing future opioid overdose fatalities that result from respiratory arrest or persistent apnea.

Background Several chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented, but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system comprises the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors. The relative prevalence of different components of the endocannabinoid system in specific brain regions may alter responses to endogenous and exogenous ligands. Methods Brain tissue from naïve male and estrous staged female Sprague Dawley rats was harvested from V1M cortex, periaqueductal gray, trigeminal nerve, and trigeminal nucleus caudalis. Tissue was analyzed for relative levels of endocannabinoid enzymes, ligands, and receptors via mass spectrometry, unlabeled quantitative proteomic analysis, and immunohistochemistry. Results Mass spectrometry revealed significant differences in 2-AG and AEA concentrations between males and females, as well as between female estrous cycle stages. Specifically, 2-AG concentration was lower within female PAG as compared to male PAG (* p  = 0.0077); female 2-AG concentration within the PAG did not demonstrate estrous stage dependence. Immunohistochemistry followed by proteomics confirmed the prevalence of 2-AG-endocannabinoid system enzymes in the female PAG. Conclusions Our results suggest that sex differences exist in the endocannabinoid system in two CNS regions relevant to cortical spreading depression (V1M cortex) and descending modulatory networks in pain/anxiety (PAG). These basal differences in endogenous endocannabinoid mechanisms may facilitate the development of chronic pain conditions and may also underlie sex differences in response to therapeutic intervention.

Introduction: Traumatic brain injury (mTBI) is a leading cause of disability in the US. Angiotensin 1-7, an endogenous peptide, acts at MAS receptors to inhibit inflammatory mediators and decrease reactive oxygen species within the CNS. Few studies have identified whether Ang-(1-7) decreases cognitive impairment following closed mTBI. Materials and Methods: Twenty-four male mice underwent a closed-skull, controlled cortical impact injury. Two hours after injury, mice were administered either Ang-(1-7) (n=12) or vehicle (n=12), continuing through day-5 post-TBI, and tested for cognitive impairment on days 1-5 and 18. pTau, Tau, GFAP, and serum cytokines were measured at multiple time points. Animals were observed daily for cognition and motor coordination via novel object recognition. Brain sections were stained and evaluated for neuronal injury. Results: Administration of Ang-(1-7) daily for five days post-mTBI significantly increased cognitive function as compared to saline control-treated animals. Cortical hippocampal structures of mice showed less damage in the presence of Ang-(1-7). Ang-(1-7) administration significantly changed the expression of pTau and GFAP in cortical and hippocampal regions as compared to control. Discussion: These are among the first studies to demonstrate that sustained administration of Ang-(1-7) following a closed-skull single impact mTBI significantly improves outcomes, potentially offering a novel therapy to prevent long-term CNS impairment.

Pre-clerkship curricula of most Liaison Committee on Medical Education (LCME)-accredited medical schools are divided into blocks by organ system, leaving a significant amount of information susceptible to loss due to prolonged nonuse. We describe the implementation of a formal Spiral Curriculum that periodically revisits material from previous blocks. Learners were surveyed on receptivity to the curriculum across three graduating classes at a single medical school. Medical school graduate classes of 2020, 2021, and 2022 were surveyed at the end of their pre-clerkship years (2018-2020). The class of 2022 actually received the Spiraled Curriculum intervention, for which the authors created 500 board exam style multiple-choice questions, periodically administered via mandatory in-class sessions ranging from 10 to 20 questions reviewing content from previous blocks with designated expert faculty. Response rates were 36% (n = 46), 45% (n = 52), and 32% (n = 40) for classes of 2020, 2021, and 2022, respectively. On a Likert scale (1 = strongly disagree, 5 = neutral, 10 = strongly agree), the classes of 2020, 2021, and 2022 provided statistically significant differences in their belief that a Spiraled Curriculum would/did help them retain information as 8.2 (SD 1.7), 8.2 (SD 2.2), and 5.0 (SD 3.0) (n < 0.05). All classes endorsed neutral confidence in the existing pre-clerkship curriculum in themselves to prepare for United Stated Medical Licensing Examination (USMLE) Step 1, and in their retention of previous block material with no statistically significant differences between classes. USMLE Step 1 scores did not differ significantly between classes (n = 0.21). Those who did not receive the Spiral Curriculum were highly receptive to it in theory, while those who actually received the intervention gave a neutral rating. Per survey comments, implementation of a Spiraling Curriculum would ideally be administered as either team-based or self-directed activities, and a Spiraling Curriculum may be difficult to implement in accelerated (18 month) pre-clerkship formats. Practice points Question: What is the receptivity of medical students to a formal Spiral curriculum that uses time-spaced repetition sessions of board exam style questions to revisit previous block content of their pre-clerkship years? Findings: In this single-center, quasi-experimental study, the two control group medical school classes had very positive theoretical reception to a Spiral curriculum proposal (rated 8 out of 10) while the class who actually received the Spiral curriculum provided a statistically significant lower neutral rating (rated 5 out of 10), citing preference for a team-based or self-directed format. Meaning: Medical students are strongly in favor of structured time-spaced repetition with board exam style questions to revisit previous material but prefer a format that does not interfere with time to personalize their medical school experience.

Disruption of blood-brain barrier integrity and dramatic failure of brain ion homeostasis including fluctuations of pH occurs during cortical spreading depression (CSD) events associated with several neurological disorders, including migraine with aura, traumatic brain injury and stroke. NHE1 is the primary regulator of pH in the central nervous system. The goal of the current study was to investigate the role of sodium-hydrogen exchanger type 1 (NHE1) in blood brain barrier (BBB) integrity during CSD events and the contributions of this antiporter on xenobiotic uptake. Using immortalized cell lines, pharmacologic inhibition and genetic knockdown of NHE1 mitigated the paracellular uptake of radiolabeled sucrose implicating functional NHE1 in BBB maintenance. In contrast, loss of functional NHE1 in endothelial cells facilitated uptake of the anti-migraine therapeutic, sumatriptan. In female rats, cortical KCl but not aCSF selectively reduced total expression of NHE1 in cortex and PAG but increased expression in trigeminal ganglia; no changes were seen in trigeminal nucleus caudalis. Thus, in vitro observations may have a significance in vivo to increase brain sumatriptan levels. Pharmacological inhibition of NHE1 prior to cortical manipulations enhanced the efficacy of sumatriptan at early time-points but induced facial sensitivity alone. Overall, our results suggest that dysregulation of NHE1 contributes to breaches in BBB integrity, drug penetrance, and the behavioral sensitivity to the antimigraine agent, sumatriptan.

Defective angiogenesis underlies over 50 malignant, ischemic and inflammatory disorders yet long-term therapeutic applications inevitably fail, thus highlighting the need for greater understanding of the vast crosstalk and compensatory mechanisms. Based on proteomic profiling of angiogenic endothelial components, here we report β IV -spectrin, a non-erythrocytic cytoskeletal protein, as a critical regulator of sprouting angiogenesis. Early loss of endothelial-specific β IV -spectrin promotes embryonic lethality in mice due to hypervascularization and hemorrhagic defects whereas neonatal depletion yields higher vascular density and tip cell populations in developing retina. During sprouting, β IV -spectrin expresses in stalk cells to inhibit their tip cell potential by enhancing VEGFR2 turnover in a manner independent of most cell-fate determining mechanisms. Rather, β IV -spectrin recruits CaMKII to the plasma membrane to directly phosphorylate VEGFR2 at Ser984, a previously undefined phosphoregulatory site that strongly induces VEGFR2 internalization and degradation. These findings support a distinct spectrin-based mechanism of tip-stalk cell specification during vascular development. Defective angiogenesis remains a high source of morbidity in multiple disorders. Here they show that β IV -spectrin, a membrane-associated cytoskeletal protein, is essential for regulation of endothelial tip cell populations and VEGF signaling during sprouting angiogenesis.

The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry. Studies here using proteomic analysis and quantitative real-time PCR (qRT-PCR) found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; three of these proteins or genes (PLCγ2, ABHD6, and CB2R) were significantly affected after repeated morphine exposure (CB2R was only detected by qRT-PCR but not proteomics). We also identified that repeated morphine treatment does not alter either anandamide (AEA) or 2-arachidonoylglycerol (2-AG) levels in the VTA compared to saline treatment; however, there may be diminished levels of anandamide (AEA) production in the VTA 4 h after a single morphine injection in both chronic saline and morphine pretreated cohorts. Treating the animals with an inhibitor of 2-AG degradation significantly decreased repeated opioid rewarding behavior. Taken together, our studies reveal a potential influence of sustained opioids on the endocannabinoid system in the VTA, suggesting that the endogenous cannabinoid system may participate in the opioid-induced reward.

CB 2 cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB 2 receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB 2 receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB 2 receptor-mediated inhibition of pain responses. Here, we test the hypothesis that CB 2 receptor activation stimulates release from keratinocytes of the endogenous opioid β-endorphin, which then acts at opioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB 2 receptor-selective agonist AM1241 were prevented in rats when naloxone or antiserum to β-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that β-endorphin is necessary for CB 2 receptor-mediated antinociception. Further, AM1241 did not inhibit nociception in μ-opioid receptor-deficient mice. Hindpaw injection of β-endorphin was sufficient to produce antinociception. AM1241 stimulated β-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB 2 cannabinoid receptor-selective antagonist and was not observed in skin from CB 2 cannabinoid receptor-deficient mice. These data suggest that CB 2 receptor activation stimulates release from keratinocytes of β-endorphin, which acts at local neuronal μ-opioid receptors to inhibit nociception. Supporting this possibility, CB 2 immunolabeling was detected on β-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of β-endorphin, where CB 2 receptors are present, leading to anatomical specificity of opioid effects. β-endorphin nociception pain keratinocyte skin