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Trends in Opioid Use Among Older Survivors of Colorectal, Lung, and Breast Cancers.

Cancer survivors may be at increased risk for opioid-related harms. Trends in opioid use over time since diagnosis are unknown.

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Genetic components of human pain sensitivity: a protocol for a genome-wide association study of experimental pain in healthy volunteers.

Pain constitutes a major component of the global burden of diseases. Recent studies suggest a strong genetic contribution to pain susceptibility and severity. Whereas most of the available evidence relies on candidate gene association or linkage studies, research on the genetic basis of pain sensitivity using genome-wide association studies (GWAS) is still in its infancy. This protocol describes a proposed GWAS on genetic contributions to baseline pain sensitivity and nociceptive sensitisation in a sample of unrelated healthy individuals of mixed Latin American ancestry.

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Engineering NaV1.7 Inhibitory JzTx-V Peptides with a Potency and Basicity Profile Suitable for Antibody Conjugation to Enhance Pharmacokinetics.

Drug discovery research on new pain targets with human genetic validation, including the voltage-gated sodium channel NaV1.7, is being pursued to address the unmet medical need for chronic pain and the rising opioid epidemic. As part of early research efforts on this front, we have previously developed NaV1.7 inhibitory peptide-antibody conjugates with tarantula venom-derived GpTx-1 toxin peptides with extended half-life (80 h) in rodents but only moderate in vitro activity (hNaV1.7 IC50 = 250 nM) and without in vivo activity. We identified the more potent peptide JzTx-V from our natural peptide collection and improved its selectivity against other sodium channel isoforms through positional analoging. Here we report utilization of the JzTx-V scaffold in a peptide-antibody conjugate and architectural variations in linker, peptide loading, and antibody attachment site. We found conjugates with 100x improved in vitro potency relative to complementary GpTx-1 analogs, but pharmacokinetic and bioimaging analyses of these JzTx-V conjugates revealed a shorter than expected plasma half-life in vivo with accumulation in the liver. In an attempt to increase circulatory serum levels, we sought the reduction of the net +6 charge of the JzTx-V scaffold whilst retaining a desirable NaV in vitro activity profile. The conjugate of a JzTx-V peptide analog with a +2 formal charge maintained NaV1.7 potency with 18-fold improved plasma exposure in rodents. Balancing the loss in peptide and conjugate potency associated with the reduction of net charge necessary for improved target exposure resulted in a compound with moderate activity in a NaV1.7-dependent pharmacodynamic model but requires further optimization to identify a conjugate that can fully engage NaV1.7 in vivo.

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The Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Fenobam: Pharmacokinetics, Side Effects, and Analgesic Effects in Healthy Human Subjects.

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Sensorimotor peak alpha frequency is a reliable biomarker of pain sensitivity.

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NEJM Knowledge+ Pain Management and Opioids – A New Adaptive Learning Module.

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Distinct Modes of Presynaptic Inhibition of Cutaneous Afferents and Their Functions in Behavior.

Presynaptic inhibition (PSI) of primary sensory neurons is implicated in controlling gain and acuity in sensory systems. Here, we define circuit mechanisms and functions of PSI of cutaneous somatosensory neuron inputs to the spinal cord. We observed that PSI can be evoked by different sensory neuron populations and mediated through at least two distinct dorsal horn circuit mechanisms. Low-threshold cutaneous afferents evoke a GABA-receptor-dependent form of PSI that inhibits similar afferent subtypes, whereas small-diameter afferents predominantly evoke an NMDA-receptor-dependent form of PSI that inhibits large-diameter fibers. Behaviorally, loss of either GABA receptors (GABARs) or NMDA receptors (NMDARs) in primary afferents leads to tactile hypersensitivity across skin types, and loss of GABARs, but not NMDARs, leads to impaired texture discrimination. Post-weaning age loss of either GABARs or NMDARs in somatosensory neurons causes systemic behavioral abnormalities, revealing critical roles of two distinct modes of PSI of somatosensory afferents in adolescence and throughout adulthood.

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The Mechanosensitive Ion Channel Piezo Inhibits Axon Regeneration.

Neurons exhibit a limited ability of repair. Given that mechanical forces affect neuronal outgrowth, it is important to investigate whether mechanosensitive ion channels may regulate axon regeneration. Here, we show that DmPiezo, a Ca-permeable non-selective cation channel, functions as an intrinsic inhibitor for axon regeneration in Drosophila. DmPiezo activation during axon regeneration induces local Ca transients at the growth cone, leading to activation of nitric oxide synthase and the downstream cGMP kinase Foraging or PKG to restrict axon regrowth. Loss of DmPiezo enhances axon regeneration of sensory neurons in the peripheral and CNS. Conditional knockout of its mammalian homolog Piezo1 in vivo accelerates regeneration, while its pharmacological activation in vitro modestly reduces regeneration, suggesting the role of Piezo in inhibiting regeneration may be evolutionarily conserved. These findings provide a precedent for the involvement of mechanosensitive channels in axon regeneration and add a potential target for modulating nervous system repair.

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Priming of adult incision response by early life injury: neonatal microglial inhibition has persistent but sexually dimorphic effects in adult rats.

Neonatal hindpaw incision primes developing spinal nociceptive circuitry, resulting in enhanced hyperalgesia following re-injury in adulthood. Spinal microglia contribute to this persistent effect and microglial inhibition at the time of adult re-incision blocks the enhanced hyperalgesia. Here, we pharmacologically inhibited microglial function with systemic minocycline or intrathecal SB203580 at the time of neonatal incision and evaluated sex-dependent differences following adult re-incision. Incision in adult male and female rats induced equivalent hyperalgesia and spinal dorsal horn expression of genes associated with microglial proliferation () and transformation to a reactive phenotype (). In control adults with prior neonatal incision, the enhanced degree and duration of incision-induced hyperalgesia and spinal microglial responses to re-incision were equivalent in males and females. However, microglial inhibition at the time of the neonatal incision revealed sex-dependent effects: the persistent mechanical and thermal hyperalgesia following re-incision in adulthood was prevented in males but unaffected in females. Similarly, re-incision induced and gene expression was downregulated in males, but not in females following neonatal incision with minocycline. To evaluate the distribution of re-incision hyperalgesia, prior neonatal incision was performed at different body sites. Hyperalgesia was maximal when the same paw was re-incised, and was increased following prior incision at ipsilateral, but not contralateral sites; supporting a segmentally restricted spinal mechanism. These data highlight the contribution of spinal microglial mechanisms to persistent effects of early-life injury in males, and sex-dependent differences in the ability of microglial inhibition to prevent the transition to a persistent pain state spans developmental stages. Following the same surgery, some patients develop persistent pain. Contributory mechanisms are not fully understood, but early-life experience and sex/gender may influence the transition to chronic pain. Surgery and painful procedural interventions in vulnerable preterm neonates are associated with long-term alterations in somatosensory function and pain that differ in males and females. Surgical injury in neonatal rodents primes the developing nociceptive system and enhances re-injury response in adulthood. Neuroimmune interactions are critical mediators of persistent pain, but sex-dependent differences in spinal neuroglial signaling influence the efficacy of microglial inhibitors following adult injury. Neonatal microglial inhibition has beneficial long-term effects on re-injury response in adult males only, emphasizing the importance of evaluating sex-dependent differences at all ages in pre-clinical studies.

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Neuropeptide PEN and its receptor GPR83; Distribution, Signaling and Regulation.

Neuropeptides are peptide neuromodulators that are expressed by neurons and act on neural targets by activating neuropeptide receptors1. These receptors serve as therapeutic targets for the treatment of a number of pathophysiological conditions, including obesity, pain and addiction2-6. Major technological advances in the 1980s involving improved sensitivity of peptide purification methods and single neuron mRNA sequencing techniques have led to an explosion in the number of newly discovered neuropeptides7. However, to date, receptors for many of these neuropeptides remain largely unknown. In addition, currently there are a number of "orphan" G-protein-coupled receptors (GPCRs) for which endogenous ligands or function are yet to be identified8, 9.These "orphan" neuropeptides and GPCRs represent an untapped resource for the development of therapeutics to treat chronic diseases including drug abuse disorders, obesity and neuropathic pain. With this in mind much effort has been put towards deorphanizing these "orphan" peptides/GPCRs. Here, we summarize current insights into one such relationship: that between the neuropeptide PEN and the GPCR named GPR83. This intriguing system promises to deepen our current understanding of neuropeptide/GPCR systems, but also highlights the necessity for further technological advances in order to fully understand its complexity.

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