Substance P/ Neurokinin-1 Receptor, Trigeminal Ganglion, Latency, and Coronavirus Infection-Is There Any Link?

Novel Severe Acute Respiratory Syndrome-Corona Virus-2 infection (SARS-CoV-2) is an acute respiratory and infectious disease. This perspective aims to provide a basic understanding of the inflammation caused by SARS-CoV-2 and its relation to the trigeminal ganglion (TG). The virus enters through the mucous membranes of the orofacial region and reaches the TG, where it resides and takes control of its peptides including Substance P (SP). SP is the main neuropeptide, neuromodulator, and neuro-hormone of TG, associated with nociception and inflammation under noxious stimulus. SP release is triggered and, consequently, affects the immune cells and blood vessels to release the mediators for inflammation. Hence, cytokine storm is initiated and causes respiratory distress, bronchoconstriction, and death in complicated cases. Neurokinin-1 Receptor (NK-1R) is the receptor for SP and its antagonists, along with glucocorticoids, may be used to alleviate the symptoms and treat this infection by blocking this nociceptive pathway. SP seems to be the main culprit involved in the triggering of inflammatory pathways in SARS-CoV-2 infection. It may have a direct association with cardio-respiratory rhythm, sleep-wake cycle, nociception, and ventilatory responses and regulates many important physiological and pathological functions. Its over-secretion should be blocked by NK-1R antagonist. However, experimental work leading to clinical trials are mandatory for further confirmation. Here, it is further proposed that there is a possibility of latency in SARS-CoV-2 virus infection if it is acting through TG, which is the main site for other viruses that become latent.

The impact of genetic polymorphism in pain mechanisms

Background:Variations in genes codifying target structures in the nociceptive pathway can result in pain attenuation or increase.Objective:Investigate the genetic polymorphism influence in the individual pain threshold. Methods: Search on PubMed with the terms “genetic”, “pain” and its synonyms published in the last 10 years. Results:The subjective and individual mechanisms of pain aren’t completely understood, but genetic susceptibility is one of the hypothesis to explain these differences.The KCNK18 gene influences the synaptic transmission by producing potassium channel protein that equalizes resting membrane potential, calcineurin activated and inhibited by arachidonic acid. This gene was found more frequently in migraine individuals. The COMT gene increase the sensibility to pain by met-enkephalins reduction and/or catecholamine elevation. Its activity’s reduced in fibromyalgia patients. However, the OPRM1 gene, an opioid receptor, was found in individuals with a higher pain threshold.Furthermore, studies with human cell culture shows the analgesic role of the gene A118G, by its greater binding affinity for β-endorphin.It is associated with more effective endorphinergic endogenous pain inhibition. Conclusion:Researches indicates a striking participation of genetic polymorphism in pain mechanisms. The knowledge about genetic variables on pain perception can contribute to the development of individualized analgesic protocols and therapeutic strategies, accordantly to the patient genetic profile. This evolution becomes fundamental in a population that tend to the indiscriminate use of analgesics.

ASIC3-dependent spinal cord nociceptive signaling in cutaneous pain induced by lysophosphatidyl-choline

ABSTRACTLysophosphatidyl-choline (LPC), a member of the phospholipid family, has recently emerged as an interesting new player in pain. It has been proposed to mediate pain through Acid-Sensing Ion Channel 3 (ASIC3), a pain-related channel mainly expressed in peripheral sensory neurons. LPC potentiates ASIC3 current evoked by mild acidifications, but can also activate the channel at physiological pH, and its local injection in rodents evokes ASIC3-dependent pain. We combine here in vivo recordings of spinal cord neuron activity with subcutaneous LPC injection to analyze the mechanism of action associated with the LPC-induced, ASIC3-dependent pain in peripheral and spinal cord neurons. We show that a single cutaneous injection of LPC exclusively affects the nociceptive pathway. It evokes an ASIC3-dependent short-term sensitization of nociceptive fibers that drives hyperexcitability of projecting neurons within the dorsal spinal cord without apparent central sensitization.

Anti-nociceptive and anti-inflammatory effects of stem bark extract of Ficus capensis Thunb (Moraceae) by bioactivity fractionation

Objective: This study investigated the anti-nociceptive and anti-inflammatory activities of the aqueous extract of Ficus capensis (AEFC) by bio-guided fractionation. Methods: The anti-nociceptive and anti-inflammatory effects of AEFC (250, 500, 1000 mg/kg, i.p) were assessed using acetic acid-induced writhing, hot plate, tail-flick, formalin tests, and carrageenan-induced paw oedema respectively. The AEFC was fractionated base on polarity different into butanol, ethyl acetate, and n-hexane fractions. The fractions (500 mg/kg) obtained were subjected to the same experimental procedures mentioned above. The EAF, which exerted the most productive activities, was further subjected to fractionation procedures that yielded six fractions (labeled CF1-CF6). These fractions (200 mg/kg) were tested for potential anti-nociceptive and anti-inflammatory activities. Notable antagonists (Naloxone and atropine) of nociceptive pathway were used to evaluate the mechanism of the anti-nociceptive action of F. capensis. Results and Discussion: The AEFC, BF, EAF, and CF4 caused a significant (p<0.05) reduction in the number of abdominal writhes, an increase in reaction time against the hot plate, tail-flick tests, and a significant (p<0.05) inhibition in both phases of formalin test. The AEFC, BF, EAF, CF4, and CF6 caused a significant (p<0.05) inhibition of paw oedema development due to carrageenan. Atropine significantly reversed the anti-nociceptive effect of CF4 in both phases of the formalin test. The result obtained revealed that CF4 produced central and peripheral anti-nociceptive effects, while CF6 is peripherally mediated. Conclusion: The results support the traditional uses of F. capensis in the treatment of various diseases associated with pain and inflammation. The column fraction CF4 exhibited muscarinic receptor-mediated anti-nociceptive activity.

TRP Channels in the Focus of Trigeminal Nociceptor Sensitization Contributing to Primary Headaches

Pain in trigeminal areas is driven by nociceptive trigeminal afferents. Transduction molecules, among them the nonspecific cation channels transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1), which are activated by endogenous and exogenous ligands, are expressed by a significant population of trigeminal nociceptors innervating meningeal tissues. Many of these nociceptors also contain vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P. Release of neuropeptides and other functional properties are frequently examined using the cell bodies of trigeminal neurons as models of their sensory endings. Pathophysiological conditions cause phosphorylation, increased expression and trafficking of transient receptor potential (TRP) channels, neuropeptides and other mediators, which accelerate activation of nociceptive pathways. Since nociceptor activation may be a significant pathophysiological mechanism involved in both peripheral and central sensitization of the trigeminal nociceptive pathway, its contribution to the pathophysiology of primary headaches is more than likely. Metabolic disorders and medication-induced painful states are frequently associated with TRP receptor activation and may increase the risk for primary headaches.

Mechanisms of Botulinum Toxin Type A Action on Pain

Already a well-established treatment for different autonomic and movement disorders, the use of botulinum toxin type A (BoNT/A) in pain conditions is now continuously expanding. Currently, the only approved use of BoNT/A in relation to pain is the treatment of chronic migraines. However, controlled clinical studies show promising results in neuropathic and other chronic pain disorders. In comparison with other conventional and non-conventional analgesic drugs, the greatest advantages of BoNT/A use are its sustained effect after a single application and its safety. Its efficacy in certain therapy-resistant pain conditions is of special importance. Novel results in recent years has led to a better understanding of its actions, although further experimental and clinical research is warranted. Here, we summarize the effects contributing to these advantageous properties of BoNT/A in pain therapy, specific actions along the nociceptive pathway, consequences of its central activities, the molecular mechanisms of actions in neurons, and general pharmacokinetic parameters.

Targeting Melatonin MT2 Receptors: A Novel Pharmacological Avenue for Inflammatory and Neuropathic Pain

Melatonin (MLT) has been implicated in several pathophysiological states, including pain. MLT mostly activates two G-protein coupled receptors, MT1 and MT2. In this review, we present the analgesic properties of MLT in preclinical and clinical studies, giving particular emphasis to the effects mediated by MT2 receptors and to recent investigations demonstrating the analgesic effects of MT2 receptor partial agonists in chronic and acute/inflammatory pain conditions. MT2 receptors are localized in specific brain areas, including the reticular and the ventromedial nuclei of the thalamus (part of the ascending nociceptive pathway) and the ventrolateral periaqueductal grey matter (vlPAG) (part of the descending antinociceptive pathway). MLT displays analgesic properties in several animal paradigms of chronic, acute, inflammatory and neuropathic pain; importantly, these effects are mediated by MT2 receptors since they are blocked by selective MT2 antagonists. In different pain paradigms, UCM924 and UCM765, two selective MT2 receptor partial agonists, produce analgesic effects with higher potency than MLT, thus confirming the involvement of MT2 receptors in pain. Notably, these compounds do not induce sedation and motor impairments. Although their analgesic mechanism of action is not yet completely elucidated, they act on antinociceptive descending pathways by stimulating MT2 receptors on glutamatergic neurons of the vlPAG, which in turn activate OFF cells and inhibit ON cells of the rostral ventromedial medulla (RVM). Collectively, there is strong preclinical evidence suggesting the pharmacological potential of MT2 receptor partial agonists, which also have a favorable toxicological profile. These compounds may be further developed as novel analgesic drugs.