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Spider venom-derived cysteine knot peptides are a mega-diverse class of molecules that exhibit unique pharmacological properties to modulate key membrane protein targets. Voltage-gated sodium channels (Na) are often targeted by these peptides to allosterically promote opening or closing of the channel by binding to structural domains outside the channel pore. These effects can result in modified pain responses, muscle paralysis, cardiac arrest, priapism, and numbness. Although such effects are often deleterious, subtype selective spider venom peptides are showing potential to treat a range of neurological disorders, including chronic pain and epilepsy. This review examines the structure-activity relationships of cysteine knot peptides from spider venoms that modulate Na and discusses their potential as leads to novel therapies for neurological disorders.
Learn More >Infusion of pituitary adenylate cyclase activating peptide-38 (PACAP-38) provokes migraine attacks in migraineurs and headache in non-migraineurs. Adverse events like long-lasting flushing and heat sensation can be terminated with oral antihistamine treatment, indicating the involvement of mast cell activation after PACAP-infusion. Degranulation of rat peritoneal mast cells was provoked by several isoforms of PACAP previously unknown receptor pharmacology. The effect might thus be mediated either specific splice variants of the PAC-receptor or an unknown receptor for PACAP-38. In the present study, we characterize degranulation of rat meningeal mast cells in response to PACAP-receptor ligands. Furthermore, we investigate if PACAP-38-induced mast cell degranulation is mediated PAC-receptor splice variants and/or the orphan Mas-related G-protein coupled member B3 (MrgB)-receptor. To address this, the pharmacological effect of different PACAP isoforms on meningeal mast cell degranulation was investigated in the hemisected skull model after toluidine blue staining followed by microscopic quantification. Presence of mRNA encoding PAC-receptor splice variants and the MrgB-receptor in rat mast cells was investigated by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) analysis. The effect of PACAP isoforms on PAC- and MrgB-receptor-expressing oocytes were performed by two-electrode voltage-clamp (TEVC) electrophysiology. PACAP-38 is a more potent mast cell degranulating agent than Pituitary Adenylate Cyclase Activating Peptide-27 (PACAP-27) in the meninges. Presence of mRNA encoding the PAC-receptor and its different splice variants could not be detected in peritoneal mast cells by RT-PCR, whereas the orphan MrgB-receptor, recently suggested to be a mediator of basic secretagogues-induced mast cell degranulation, was widely present. In PAC-receptor-expressing oocytes both PACAP-38, PACAP-27 and the specific PAC-receptor agonist maxadilan were equipotent, however, only PACAP-38 showed a significant degranulatory effect on mast cells. We confirmed Pituitary Adenylate Cyclase Activating Peptide(6-38) [PACAP(6-38)] to be a PAC-receptor antagonist, and we demonstrated that it is a potent mast cell degranulator and have an agonistic effect on MrgB-receptors expressed in oocytes. The present study provides evidence that PACAP-induced mast cell degranulation in rat is mediated through a putative new PACAP-receptor with the order of potency being: PACAP-38 = PACAP(6-38) > > PACAP-27 = maxadilan. The results suggest that the observed responses are mediated the orphan MrgB-receptor.
Learn More >Endometriosis has a significant cost of illness burden in Europe, UK and the USA, with the majority of costs coming from reductions in productivity. However, information is scarce on if there is a differing impact between endometriosis and other causes of chronic pelvic pain, and if there are modifiable factors, such as pain severity, that may be significant contributors to the overall burden.
Learn More >Resilience factors have been suggested as key mechanisms in the relation between symptoms and disability among individuals with chronic pain. However, there is a need to better operationalize resilience and to empirically evaluate its role and function. The present study examined psychological flexibility as a resilience factor in relation to symptoms and functioning among 252 adults with chronic pain applying for participation in a digital ACT-based self-help treatment. Participants completed measures of symptoms (pain intensity, and anxiety), functioning (pain interference and depression), as well as the hypothesized resilience factor psychological flexibility (measured as avoidance, value obstruction, and value progress). As expected, symptoms, functioning and resilience factors were significantly associated. Hierarchical linear regression analyses showed that psychological flexibility significantly contributed to the prediction of pain interference and depression when adjusting for age, pain and anxiety. Also, participants with low levels of psychological flexibility were more likely to be on sick leave. Furthermore, a series of multiple mediation analyses showed that psychological flexibility had a significant indirect effect on the relationship between symptoms and functioning. Avoidance was consistently shown to contribute to the indirect effect. Results support previous findings and suggest the importance of psychological flexibility as a resilience factor among individuals with chronic pain and anxiety.
Learn More >In recent years, several melatonin (MLT) receptor agonists have been approved by FDA for the treatment of sleep disorders and depression. Very few studies have shed light on their efficacy against neuropathic pain (NP). IIK-7 is an MT-2 agonist known to promote sleep. Whether IIK-7 suppresses NP has not been reported, and the signaling profile is unknown.
Learn More >Transcranial Direct Current Stimulation (tDCS) and Transcranial Magnetic Stimulation (TMS) have been described as promising alternatives to treat different pain syndromes. This study evaluated the effects of TMS and tDCS in the treatment of chronic orofacial pain, through a systematic review.
Learn More >Using a high resolution hybridization technique we have measured , , and transcripts in mouse dorsal root ganglion (DRG) neurons. Consistent with previous studies, transcripts were highly expressed in DRG neurons of all sizes, including most notably the largest diameter neurons implicated in mediating touch and proprioception. In contrast, transcripts were selectively expressed in smaller DRG neurons, which are implicated in mediating nociception. Moreover, the small neurons expressing were mostly distinct from those neurons that strongly expressed , one of the channels implicated in heat-nociception. Interestingly, while and expressing neurons form essentially non-overlapping populations, showed co-expression in both populations. Using an functional test for the selective expression, we found that Yoda1, a PIEZO1-specific agonist, induced a mechanical hyperalgesia that displayed a significantly prolonged time course compared with that induced by capsaicin, a TRPV1-specific agonist. Taken together, our results indicate that PIEZO1 should be considered a potential candidate in forming the long sought channel mediating mechano-nociception.
Learn More >The Cannabis plant has been used for many of years as a medicinal agent in the relief of pain and seizures. It contains approximately 540 natural compounds including more than 100 that have been identified as phytocannabinoids due to their shared chemical structure. The predominant psychotropic component is Δ-tetrahydrocannabinol (Δ-THC), while the major non-psychoactive ingredient is cannabidiol (CBD). These compounds have been shown to be partial agonists or antagonists at the prototypical cannabinoid receptors, CB1 and CB2. The therapeutic actions of Δ-THC and CBD include an ability to act as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds and as protective agents in neurodegeneration. However, there is a lack of well-controlled, double blind, randomized clinical trials to provide clarity on the efficacy of either Δ-THC or CBD as therapeutics. Moreover, the safety concerns regarding the unwanted side effects of Δ-THC as a psychoactive agent preclude its widespread use in the clinic. The legalization of cannabis for medicinal purposes and for recreational use in some regions will allow for much needed research on the pharmacokinetics and pharmocology of medical cannabis. This brief review focuses on the use of cannabis as a medicinal agent in the treatment of pain, epilepsy and neurodegenerative diseases. Despite the paucity of information, attention is paid to the mechanisms by which medical cannabis may act to relieve pain and seizures.
Learn More >Sensory neurons with cell bodies situated in dorsal root ganglia convey information from external or internal sites of the body such as actual or potential harm, temperature or muscle length to the central nervous system. In recent years, large investigative efforts have worked toward an understanding of different types of DRG neurons at transcriptional, translational, and functional levels. These studies most commonly rely on data obtained from laboratory animals. Human DRG, however, have received far less investigative focus over the last 30 years. Nevertheless, knowledge about human sensory neurons is critical for a translational research approach and future therapeutic development. This review aims to summarize both historical and emerging information about the size and location of human DRG, and highlight advances in the understanding of the neurochemical characteristics of human DRG neurons, in particular nociceptive neurons.
Learn More >We bilaterally injected 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats and developed bilateral Parkinson's disease (PD) model rats in order to experimentally investigate the neural mechanisms underlying the alteration of nociception in the orofacial region of patients with PD. We explored the effects of dopamine depletion on nociception by investigating behavioral responses (face rubbing) triggered by subcutaneous administration of formalin into the vibrissa pad. We also assessed the number of c-Fos-immunoreactive (c-Fos-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Subcutaneous formalin administration evoked a two-phase increase in face rubbing. We observed the first increase 0-5 min after formalin administration (first phase) and the second increase 10-60 min after administration (second phase). The number of face rubbing behaviors of 6OHDA-injected rats did not significantly change compared with saline-injected rats in both phases. Significant increase of c-Fos-IR cells in the Vc was found in 6-OHDA-injected rats after formalin administration compared with those in saline-injected rats after formalin administration. We also assessed expression of c-Fos-IR cells in the paraventricular nucleus (PVN), and significant decrease of c-Fos-IR cells in the PVN of 6-OHDA-injected rats was found. Taken together, these findings suggest that bilateral dopaminergic denervation evoked by 6-OHDA administration causes hyperalgesia in the trigeminal region and the PVN may be involved in the hyperalgesia.
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