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Kappa opioid receptor (KOR) agonists produce robust analgesia with minimal abuse liability and are considered promising pharmacological agents to manage chronic pain and itch. The KOR system is also notable for robust differences between the sexes, with females exhibiting lower analgesic response than males. Sexually dimorphic traits can be due to either the influence of gonadal hormones during development or adulthood, or due to the complement of genes expressed on the X or Y chromosome. Previous studies examining sex differences in KOR antinociception have relied on surgical or pharmacological manipulation of the gonads to determine whether sex hormones influence KOR function. While there are conflicting reports whether gonadal hormones influence KOR function, no study has examined these effects in context with sex chromosomes. Here, we use two genetic mouse models, the four core genotypes and XY*, to isolate the chromosomal and hormonal contributions to sex differences in KOR analgesia. Mice were treated with systemic KOR agonist (U50,488H) and thermal analgesia measured in the tail withdrawal assay. We found that KOR antinociception was influenced predominantly by the number of the X chromosomes. These data suggest that the dose and/or parental imprint on X gene(s) contribute significantly to the sexually dimorphism in KOR analgesia.
Learn More >Life-long pain is a hallmark feature of sickle cell disease (SCD). How sickle pathobiology evokes pain remains unknown. We hypothesize that increased cell-free heme due to ongoing hemolysis activates toll-like receptor 4 (TLR4), leading to the formation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Together, these processes lead to spinal microglial activation and neuroinflammation culminating in acute and chronic pain.
Learn More >Traditional pain management after total knee arthroplasty (TKA) relies heavily on opioids. Although there is evidence that in-hospital multimodal pain management (MMPM) is more effective than opioid-only (OO) analgesia, there has been little focus on postdischarge pain management. The hypothesis of this study was that MMPM after TKA would reduce pain scores and opioid consumption in the 30-day period after hospital discharge.
Learn More >Chronic pain negatively affects psychological functioning including self-perception. Self-compassion may improve self-related functioning in patients with chronic pain but understanding of the neural mechanisms is limited. In this study, twenty patients with chronic low back pain read negative self-related situations and were instructed to be either self-reassuring or self-critical while undergoing fMRI. Patients rated their feelings of self-reassurance and self-criticism during each condition, and brain responses were contrasted with neutral instructions. Trait self-compassion measures (SCS) were also acquired. Brain activations during self-criticism and self-reassurance were localized to prefrontal, self- and emotion-processing areas, such as medial prefrontal cortex, dorsolateral prefrontal cortex (dlPFC), dorsal anterior cingulate cortex and posterior cingulate cortex. Self-reassurance resulted in more widespread and stronger activations relative to self-criticism. Patients then completed a brief self-compassion training (8 contact hours, 2 weeks home practice). Exploratory pre-post comparisons in thirteen patients found that feelings of self-criticism were significantly reduced and brain activations were greater in the anterior insula and prefrontal cortical regions such as dlPFC. Pre-post increases in dlPFC activation correlated with increased self-compassion (SCS), suggesting that early self-compassion skills might primarily target self-criticism via dlPFC upregulation. Future controlled studies on self-compassion training in chronic pain populations should extend these results.
Learn More >The management of persistent postsurgical pain and neuropathic pain remains a challenge in the clinic. Local anesthetics have been widely used as simple and effective treatment for these two disorders, but the duration of their analgesic effect is short. We here reported a new poly lactic-co-glycolic acid (PLGA)-coated ropivacaine that was continuously released in vitro for at least 6 days. Peri-sciatic nerve injection of the PLGA-coated ropivacaine attenuated paw incision-induced mechanical allodynia and heat hyperalgesia during the incisional pain period, and spared nerve injury-induced mechanical and cold allodynia for at least 7 days post-injection. This effect was dose-dependent. Peri-sciatic nerve injection of the PLGA-coated ropivacaine did not produce detectable inflammation, tissue irritation, or damage in the sciatic nerve and surrounding muscles at the injected site, dorsal root ganglion, spinal cord or brain cortex, although the scores for grasping reflex were mildly and transiently reduced in the higher dosage-treated groups. Perspective: Given that PLGA is an FDA-approved medical material, and that ropivacaine is used currently in clinical practice, the injectable PLGA-coated ropivacaine represents a new and highly promising avenue in the management of postsurgical pain and neuropathic pain.
Learn More >We provided strong proof of concept evidence that somatostatin mediates potent analgesic and anti-inflammatory actions via its receptor subtype 4 (sst) located both at the periphery and the central nervous system. Therefore, sst agonists are promising novel drug candidates for neuropathic pain and neurogenic inflammation, but rational drug design was not possible due to the lack of knowledge about its 3-dimensional structure. We modeled the sst receptor structure, described its agonist binding properties, and characterized the binding of our novel small molecule sst agonists (4-phenetylamino-7H-pyrrolo[2,3-d]pyrimidine derivatives) using an in silico platform. In addition to the in silico binding data, somatostatin displacement by Compound 1 was demonstrated in the competitive binding assay on sst-expressing cells. In vivo effects were investigated in rat models of neurogenic inflammation and chronic traumatic neuropathic pain. We defined high- and low-affinity binding pockets of sst for our ligands, binding of the highest affinity compounds were similar to that of the reference ligand J-2156. We showed potent G-protein activation with the highest potency of 10 nM EC value and highest efficacy of 342%. Oral administration of 100 μg/kg of 5 compounds significantly inhibited acute neurogenic plasma protein extravasation in the paw skin by 40-60%, one candidate abolished and 3 others diminished sciatic nerve-ligation induced neuropathic hyperalgesia by 28-62%. The in silico predictions on sst-ligands were tested in biological systems. Low oral dose of our novel agonists inhibit neurogenic inflammation and neuropathic pain, which opens promising drug developmental perspectives for these unmet medical need conditions.
Learn More >Diabetic peripheral neuropathic pain (DPNP), the most debilitating complication of diabetes mellitus, is resistant to current therapy. The pathogenesis of DPNP is still elusive, but several mechanisms have been proposed including abnormal hyperexcitability of dorsal root ganglion (DRG) neurons. The underlying molecular mechanisms of such aberrant hyperexcitability are incompletely understood. Using the streptozotocin (STZ) rat model of DPNP, we have recently provided evidence implicating neuronal K7 channels that normally exert a powerful stabilizing influence on neuronal excitability, in the abnormal hyperexcitability of DRG neurons and in pain hypersensitivity associated with DPNP. In the present immunohistochemical study, we sought to determine whether K7.2 and/or K7.5 channel expression is altered in DRG neurons in STZ rats. We found 35 days post-STZ: (1) a significant decrease in K7.5-immunoreactivity in small (<30 µm) DRG neurons (both IB4 positive and IB4 negative) and medium-sized (30-40 µm) neurons, and (2) a significant increase in K7.2-immunoreactivity in small (<30 µm) neurons, and a non-significant increase in medium/large neurons. The decrease in K7.5 channel expression in small and medium-sized DRG neurons in STZ rats is likely to contribute to the mechanisms of hyperexcitability of these neurons and thereby to the resulting pain hypersensitivity associated with DPNP. The upregulation of K7.2 subunit in small DRG neurons may be an activity dependent compensatory mechanism to limit STZ-induced hyperexcitability of DRG neurons and the associated pain hypersensitivity. The findings support the notion that K7 channels may represent a novel target for DPNP treatment.
Learn More >Computational models of pain consider how the brain processes nociceptive information and allow mapping neural circuits and networks to cognition and behaviour. To date, they have generally have assumed two largely independent processes: perceptual inference, typically modelled as an approximate Bayesian process, and action control, typically modelled as a reinforcement learning process. However, inference and control are intertwined in complex ways, challenging the clarity of this distinction. Here, we consider how they may comprise a parallel hierarchical architecture that combines inference, information-seeking, and adaptive value-based control. This sheds light on the complex neural architecture of the pain system, and takes us closer to understanding from where pain 'arises' in the brain.
Learn More >Although cortical spreading depolarizations (CSD) were originally assumed to be homogeneously and concentrically propagating waves, evidence obtained first in gyrencephalic brains and later in lissencephalic brains suggested a rather non-uniform propagation, shaped heterogeneously by factors like cortical region differences, vascular anatomy, wave recurrences and refractory periods. Understanding this heterogeneity is important to better evaluate the experimental models on the mechanistics of CSD and to make appropriate clinical estimations on neurological disorders like migraine, stroke, and traumatic brain injury. This study demonstrates the application of optical flow analysis tools for systematic and objective evaluation of spatiotemporal CSD propagation patterns in anesthetized mice and compares the propagation profile in different CSD induction models. Our findings confirm the asymmetric angular CSD propagation in lissencephalic brains and suggest a strong dependency on induction-method, such that continuous potassium chloride application leads to significantly higher angular propagation variability compared to optogenetically-induced CSDs.
Learn More >Transient receptor potential melastatin 8 (TRPM8) ion channel represents a valuable pharmacological option for several therapeutic areas. Here, a series of conformationally restricted derivatives of the previously described TRPM8 antagonist N,N'-dibenzyl tryptophan were prepared and characterized in vitro by Ca-imaging and patch-clamp electrophysiology assays. Molecular modeling studies led to identification of a broad and well-defined interaction network of these derivatives inside the TRPM8-agonist binding site, underlying their antagonist activity. The (5R,11aS)-5-(4-chlorophenyl)-2-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione () emerged as a potent (IC50 4.10 ± 1.2 nM), selective, and metabolically stable TRPM8 antagonist. In vivo, showed significant target coverage in an icilin-induced WDS (at 11.5 mg/kg i.p.), an oxaliplatin-induced cold allodynia (at 10-30 μg s.c.), and CCI-induced thermal hyperalgesia (at 11.5 mg/kg i.p.) mice models. These results confirm the tryptophan moiety as a solid pharmacophore template for the design of highly potent modulators of TRPM8-mediated activities.
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