The role of K-channels in the formation of a nociceptive signal in the rat trigeminal nerve

The central problem of this work is to elucidate the mechanisms of pain in migraine and to establish the role of Kv channels in regulating the excitability of meningeal afferents of the trigeminal nerve that form a pain signal in migraine. The study was conducted on a preparation of an isolated rat skull. It was found that Kv-channel inhibitors 4-aminopyridine (100 microns and 1 mM) and tetraethylammonium (5mm) lead to an increase in the excitability of trigeminal nerve afferents, at the same time, this effect was partially removed by a nonsteroidal anti–inflammatory agent - naproxen, and was not sensitive to sumatriptan, a classic anti-migraine drug. Key words: migraine, K-channels, trigeminal nerve, 4-aminopyridine, tetraethylammonium, naproxen, sumatriptan.

The parabrachial-to-amygdala pathway provides aversive information to induce avoidance behavior in mice

The neuronal circuitry for pain signals has been intensively studied for decades. The external lateral parabrachial nucleus (PB) was shown to play a crucial role in nociceptive information processing. Previous work, including ours, has demonstrated that stimulating the neuronal pathway from the PB to the central region of the amygdala (CeA) can substitute for an actual pain signal to drive an associative form of threat/fear memory formation. However, it is still unknown whether activation of the PB–CeA pathway can directly drive avoidance behavior, escape behavior, or only acts as strategic freezing behavior for later memory retrieval. To directly address this issue, we have developed a real-time Y-maze conditioning behavioral paradigm to examine avoidance behavior induced by optogenetic stimulation of the PB–CeA pathway. In this current study, we have demonstrated that the PB–CeA pathway carries aversive information that can directly trigger avoidance behavior and thereby serve as an alarm signal to induce adaptive behaviors for later decision-making.

Engineering Microneedle Patches for Improved Penetration: Analysis, Skin Models and Factors Affecting Needle Insertion

Transdermal microneedle (MN) patches are a promising tool used to transport a wide variety of active compounds into the skin. To serve as a substitute for common hypodermic needles, MNs must pierce the human stratum corneum (~ 10 to 20 µm), without rupturing or bending during penetration. This ensures that the cargo is released at the predetermined place and time. Therefore, the ability of MN patches to sufficiently pierce the skin is a crucial requirement. In the current review, the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared. This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice. Factors that affect insertion (e.g., geometry, material composition and cross-linking of MNs), along with recent advancements in developed strategies (e.g., insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography) to improve the skin penetration are highlighted to provide a backdrop for future research.

Reasons for Delayed Pain Management in Patients With Chronic Migraine: A Qualitative Study

Background: Chronic migraine is often perceived as complex disease and difficult to manage. People with episodic migraine run the risk of developing chronic migraine, leading to great suffering for themselves, their families, and the larger society. The management of each attack may influence the development from episodic to chronic migraine. Aim: The aim of the present study was to explore experiences and management of migraine pain in patients with chronic migraine. Methods: Ten migraine patients participated in open interviews based on functional behavioural analysis within a cognitive behavioural framework. The interviews were analysed using systematic text condensation. Results: Participants’ experiences and management of chronic migraine pain was categorized under four concepts: Migraine pain signal, Hope of false alarm, Guiding assumption, and Delayed medical management. Conclusions: Difficulty distinguishing early migraine pain from other pain signals, neglect of migraine pain signals, and assumption of pain management can lead to delays in initiating emergency medication. Potentially early response to migraine pain signals could alleviate attacks.

Inflammatory Mediators and Pain in Endometriosis: A Systematic Review

Background: pain is one of the main symptoms of endometriosis and it has a deleterious effect on a patients’ personal and social life. To date, the clinical management of pain includes prolonged medication use and, in some cases, surgery, both of which are disruptive events for patients. Hence, there is an urgency for the development of a sufficient non-invasive medical treatment. Inflammation is one of the causative factors of pain in endometriosis. It is well established that inflammatory mediators promote angiogenesis and interact with the sensory neurons inducing the pain signal; the threshold of pain varies and it depends on the state and location of the disease. The inhibition of inflammatory mediators’ synthesis might offer a novel and effective treatment of the pain that is caused by inflammation in endometriosis. Objectives: patients with endometriosis experience chronic pelvic pain, which is moderate to severe in terms of intensity. The objective of this systematic review is to highlight the inflammatory mediators that contribute to the induction of pain in endometriosis and present their biological mechanism of action. In addition, the authors aim to identify new targets for the development of novel treatments for chronic pelvic pain in patients with endometriosis. Data Sources: three databases (PubMed, Scopus, and Europe PMC) were searched in order to retrieve articles with the keywords ‘inflammation, pain, and endometriosis’ between the review period of 1 January 2016 to 31 December 2020. This review has been registered with PROSPERO (registry number: CRD42020171018). Eligibility Criteria: only original articles that presented the regulation of inflammatory mediators and related biological molecules in endometriosis and their contribution in the stimulation of pain signal were included. Data Extraction: two authors independently extracted data from articles, using predefined criteria. Results: the database search yielded 1871 articles, which were narrowed down to 56 relevant articles of interest according to the eligibility criteria. Conclusions: inflammatory factors that promote angiogenesis and neuroangiogenesis are promising targets for the treatment of inflammatory pain in endometriosis. Specifically, CXC chemokine family, chemokine fractalkine, and PGE2 have an active role in the induction of pain. Additionally, IL-1β appears to be the primary interleukin (IL), which stimulates the majority of the inflammatory factors that contribute to neuroangiogenesis along with IL-6. Finally, the role of Ninj1 and BDNF proteins needs further investigation.

The brinker repressor system regulates injury-induced nociceptive sensitization in Drosophila melanogaster

Chronic pain is a debilitating condition affecting millions of people worldwide, and an improved understanding of the pathophysiology of chronic pain is urgently needed. Nociceptors are the sensory neurons that alert the nervous system to potentially harmful stimuli such as mechanical pressure or noxious thermal temperature. When an injury occurs, the nociceptive threshold for pain is reduced and an increased pain signal is produced. This process is called nociceptive sensitization. This sensitization normally subsides after the injury is healed. However, dysregulation can occur which results in sensitization that persists after the injury has healed. This process is thought to perpetuate chronic pain. The Hedgehog (Hh) signaling pathway has been previously implicated in nociceptive sensitization in response to injury in Drosophila melanogaster. Downstream of Hh signaling, the Bone Morphogenetic Protein (BMP) pathway has also been shown to be necessary for this process. Here, we describe a role for nuclear components of BMP’s signaling pathway in the formation of injury-induced nociceptive sensitization. Brinker (Brk), and Schnurri (Shn) were suppressed in nociceptors using an RNA-interference (RNAi) “knockdown” approach. Knockdown of Brk resulted in hypersensitivity in the absence of injury, indicating that it normally acts to suppress nociceptive sensitivity. Animals in which transcriptional activator Shn was knocked down in nociceptors failed to develop normal allodynia after ultraviolet irradiation injury, indicating that Shn normally acts to promote hypersensitivity after injury. These results indicate that Brk-related transcription regulators play a crucial role in the formation of nociceptive sensitization and may therefore represent valuable new targets for pain-relieving medications.

Treatment of Déjerine–Roussy syndrome pain with scrambler therapy

Aim: Déjerine–Roussy syndrome or central thalamic pain can be devastating, and treatment with drugs and even deep brain stimulation can be unsatisfactory. Scrambler therapy is a form of neuromodulation that uses external skin electrodes to send a ‘non-pain’ signal to the brain, with some success in difficult-to-treat syndromes such as neuromyelitis optica spectrum disorder. We used scrambler therapy to treat a patient with 6 years of disabling Déjerine–Roussy syndrome pain. Methods: A 56-year-old man received multiple daily then monthly treatments with electrode pairs placed just above the area of distal pain. Each treatment was for 40 min. Results: His allodynia and hyperalgesia resolved within 10 min, and his pain score fell to almost zero after 30 min. Months later, he resumed normal activity and is off all his pain medications. No side effects were noted. Conclusion: Scrambler therapy appeared to reverse 6 years of disabling pain safely and economically, and continues to be effective. Further multi-institutional trials are warranted for this rare syndrome.

Protection of flunarizine on ventralis posteromedialis nucleus in rat model of migraine induced by inflammatory soup

Background: Migraine is a disease closely related to calcium ions and ion channels. Ventralis posteromedialis (VPM) nucleus is an important nucleus in the process of migraine pain signal transmission. Flunarizine has been widely demonstrated as a calcium channel antagonist in the preventive treatment of migraine, but the mechanism of its anti-migraine on VPM is still unclear. Methods: Part 1. Fifteen transfected male rats were randomly divided into three groups: Flunarizine intervention group, Nimodipine intervention group and Normal saline sham group. Viral expression of fluorescent tracers allows purely anterograde labeling. Following injection of AAV-hSyn-9-CaMPARI-GFP into the physiologically defined area in the VPM nucleus of the thalamus, labeling in the thalamus-cortex had a green appearance. Part 2. Twenty Sprague Dawley male rats were randomly divided into four groups: Single stimulus group, Double stimuli group, Flunarizine intervention group and Nimodipine intervention group. A calcium-selective carbon fiber electrode (CFMEs) is used for online monitoring of electrochemically inactive Ca2+ in the rat brain in vivo. Results: Part 1.GFP Images showed that the VPM nucleus of the thalamus was involved in the signal transmission process of headache. Fluorescence imaging of the VPM nucleus of the thalamus after intervention with flunarizine or nimodipine suggested that it was activated. Part 2. No specific response was observed in the migraine rat model after stimulation with normal saline, extracellular calcium ions increased first and then decreased linearly after each stimulation with inflammatory soup. After the intervention of nimodipine, the curve of calcium changes after IS stimulation was the same as before. While after the intervention of flunarizine, the performance was significantly inconsistent, which was first increased and then maintained a level of concentration or slightly increased. Conclusion: VPM might play an important role in pain signal transmission of migraine and Flunarizine can alleviate such Ca2+ concentration in VPM neurons to exert its anti-migraine effects.

Maladaptive activation of Nav1.9 channels by nitric oxide causes triptan-induced medication overuse headache

Medication-overuse headaches (MOH) occur with both over-the-counter and pain-relief medicines, including paracetamol, opioids and combination analgesics. The mechanisms that lead to MOH are still uncertain. Here, we show that abnormal activation of Nav1.9 channels by Nitric Oxide (NO) is responsible for MOH induced by triptan migraine medicine. Deletion of the Scn11a gene in MOH mice abrogates NO-mediated symptoms, including cephalic and extracephalic allodynia, photophobia and phonophobia. NO strongly activates Nav1.9 in dural afferent neurons from MOH but not normal mice. Abnormal activation of Nav1.9 triggers CGRP secretion, causing artery dilatation and degranulation of mast cells. In turn, released mast cell mediators potentiates Nav1.9 in meningeal nociceptors, exacerbating inflammation and pain signal. Analysis of signaling networks indicates that PKA is downregulated in trigeminal neurons from MOH mice, relieving its inhibitory action on NO-Nav1.9 coupling. Thus, anomalous activation of Nav1.9 channels by NO, as a result of chronic medication, promotes MOH.

THE EFFECTIVENESS OF TENS IN REDUCING THE PAIN LEVELS AMONGST WOMEN IN THE FIRST STAGE OF GIVE BIRTH

The TENS instrument is a tool as an alternative of the non-pharmacological therapies to help give birth women in dealing with pain. There are electrodes in this tool that are useful for channeling electric wave to women’s back, that it stimulates the nerves in the area pain. The signal from TENS serves to disrupt the pain signals that affect the nerves and break the pain signal, as a result reducing patients’ pain levels. The aim of the study was to find out the effectiveness of TENS towards decreasing pain levels in the first stage of labour. The study applied the quasi-experimental research method with the one group pre-test design approach. The population was women the first stage of labour, and samples were selected using the accidental sample technique, and five women participated in this study. Data were analysed using the dependent T test. The results of the study obtained TENS with a frequency of 108 Hz and a voltage of 82 Volt is safe to patients’ skin. There was not a significant effect of TENS to the level of pain with ρ-value 0.374. It can be concluded that the TENS instrument that designed in this study is ineffective in managing labor pain especially the first stage. There is a need further research to test this instrument in the laboratory, and redesign it related to the instrument size and packaging.Keywords: give birth, pain, TENS