Mol Pain
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The capsular part of the central amygdala (CeC) is called the "nociceptive amygdala," as it receives nociceptive information from various pathways, including monosynaptic input from the lateral part of the parabrachial nucleus (LPB), a major target of ascending neurons in the spinal and medullary dorsal horn. LPB-CeC synaptic transmission is mediated by glutamate but the fibers from the LPB also contain calcitonin gene-related peptide (CGRP) and the CeC is rich in CGRP-binding sites. CGRP might be released in response to strong nociception and activate these CGRP receptors. ⋯ Thus, we evaluated the effects of CGRP on NMDA-R-mediated EPSCs that were pharmacologically isolated in brain slices from naïve mice. CGRP significantly increased the amplitude of EPSCs mediated by NMDA-Rs in a manner dependent on protein kinase A activation, but not that mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, in concentration-dependent and antagonist-sensitive manners. This CGRP-induced potentiation of synaptic NMDA-R function would have a potent impact on the strengthening of the nociception-emotion link in persistent pain.
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Cancer is the second leading cause of death worldwide and is a major global health burden. Significant improvements in survival have been achieved, due in part to advances in adjuvant antineoplastic chemotherapy. The most commonly used antineoplastics belong to the taxane, platinum, and vinca alkaloid families. ⋯ The processes that underlie chemotherapy-induced changes in ion channel expression and function are poorly understood. Not all antineoplastic agents directly affect ion channel function, suggesting additional pathways may contribute to the development of CPIN Indeed, there are indications that these drugs may mediate their effects through cellular signaling pathways including second messengers and inflammatory cytokines. Here, we focus on ion channelopathies as causal mechanisms for CPIN and review the data from both pre-clinical animal models and from human studies with the aim of facilitating the development of appropriate strategies to prevent and/or treat CPIN.
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Although decanoic acid (DA) is thought to act as a muscarinic cholinergic agonist, effect of DA on nociceptive behavioral responses and the excitability of nociceptive neuronal activity under in vivo conditions remain to be determined. The aim of the present study, therefore, was to investigate whether in vivo acute administration of ointment containing DA affects the excitability of nociceptive trigeminal spinal nucleus caudalis (SpVc) neurons associated with hypoalgesia in naïve rats. ⋯ These results suggest that acute DA application induces short-term mechanical hypoalgesia and this effect was mainly due to suppression of the excitability of SpVc WDR neurons via the peripheral M2 receptor signaling pathway in the trigeminal primary afferents. These findings support the idea that DA is a potential therapeutic agent and complementary alternative medicine for the attenuation of trigeminal nociception in the absence of inflammatory/neuropathic conditions.
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Background AYX1 is an unmodified DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose at the time of surgery. AYX1 inhibits the transcription factor early growth response protein 1, which is transiently induced at the time of injury and triggers gene regulation in the dorsal root ganglia and spinal cord that leads to long-term sensitization and pain. This work characterizes the AYX1 dose-response profile in rats and the link to AYX1 pharmacokinetics and metabolism in the cerebrospinal fluid, dorsal root ganglia, and spinal cord. ⋯ Chemically, AYX1 is unprotected against degradation by nucleases. The sensitivity to nucleases is reflected in a paradoxical reduction of efficacy in the dose-response curve. Conclusions These findings point to the importance of the nuclease environment of the cerebrospinal fluid to the research and development of AYX1 and other intrathecal nucleotide-based therapeutics.
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Tight whole-cell patch clamp was performed in 191 DiI (1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate) retrogradely labeled rat sensory afferents from skin shoulders ( n = 93) and biceps femoris muscles ( n = 98). 5-HT-gated inward currents were evoked with 50-µM serotonin (5-HT; 5-hydroxytryptamine), and their frequency and current densities were compared between skin and skeletal muscle sensory afferents. To evaluate if 5-HT-gated inward currents coexist with other ligand-gated currents, the skin and skeletal muscle sensory afferents were also sequentially exposed to external solution at pH 6.8, ATP (50 µM), and capsaicin (1 µM). 5-HT evoked inward currents in 72% (67 of 93) of hairy skin sensory afferents and in only 24% (24 of 98) of skeletal muscle sensory afferents, and this difference was statistically significant ( p < 0.0000, chi-square test). The current densities obtained in hairy skin and skeletal muscle sensory afferents were not significantly different. ⋯ These results indicate that 5-HT-gated inward currents are three times more frequently evoked in small- to medium-sized sensory afferents (25-40 µm) innervating the hairy skin than on those innervating the skeletal muscle. When cells were gathered in two clusters, the difference was four times larger in the small-sized cluster (25-32 µm) and two times larger in the medium-sized cluster (33-40 µm). The results can be explained if the superficial somatic (cutaneous) nociceptive system is more exposed than the deep somatic nociceptive system (musculoskeletal) to physical and chemical stimuli inducing 5-HT-mediated inflammatory pain.