Biology subjects

Akopian, A.

Publications and source records attributed to Akopian, A..

6 recordsLinked to original sources

bioRxiv2025

Modeling Masticatory Myalgia to Headache-like Referred Pain Triggers Local Gene Plasticity at Referred Pain Sites

Patients with myofascial pain in the head and neck area report widespread and referred pain, including headache. Existing preclinical models fail to replicate this clinical phenotype; therefore, we aimed to develop animal models mimicking referred pain phenomenon and investigate whether referred pain leads to gene plasticity at the referred sites. We modeled masticatory myalgia by stimulation of either the masseter (MM) or temporal muscle (TM) in mice. MM and TM were stimulated with a single high-dose injection of Collagenase-type II (Col), repetitive low-dose Col injections, repetitive gentle MM stimulation, or single or repetitive forceful mouth opening. Referred pain was assessed by measuring mechanical hypersensitivity in the periorbital area (representing headache-like behavior) and another masticatory muscle. Stimulation of the MM, whether through single or repetitive Col injections or mouth opening, produced inconsistent, short-lasting (1-2 days) headache-like behavior in both males and females. In contrast, stimulation of the TM, using different paradigms, triggered mechanical hypersensitivity in both the MM and the periorbital area. Referred headache-like behavior lasted longer in females compared to males, while referred myalgia in the MM was pronouncer in males. The referred pain in the MM and periorbital areas triggered by TM stimulation was associated with significant gene plasticity in the MM and dura mater. Transcriptional changes in the MM following Col injection into the TM resembled those observed after direct MM injections. Presented data imply that referred pain modeled by TM stimulation could be accounted by nociceptive signaling from multiple local sites involved in this referred pain network.

neuroscience↗

bioRxiv2024

Degenerative and regenerative peripheral processes are associated with persistent painful chemotherapy-induced neuropathies in males and females

This study aimed to investigate the time course of gene expression changes during the progression of persistent painful neuropathy caused by paclitaxel (PTX) in male and female mouse hind paws and dorsal root ganglia (DRG). Bulk RNA-seq was used to investigate the gene expression changes in the paw and DRG collected at 1, 16, and 31 days post-PTX. At these time points, differentially expressed DEGs were predominantly related to reduction or increase in epithelial, skin, bone, and muscle development and to angiogenesis, myelination, axonogenesis, and neurogenesis. These processes were accompanied by regulation of DEGs related to cytoskeleton, extracellular matrix organization and cellular energy production. This gene plasticity during persistent painful neuropathy progression likely represents biological processes linked to tissue regeneration and degeneration. Unlike regeneration/degeneration, gene plasticity related to immune processes was minimal at 1-31 days post-PTX. It was also noted that despite similarities in biological processes and pain chronicity in males and females, specific DEGs showed dramatic sex-dependency. The main conclusions of this study are that gene expression plasticity in paws and DRG during PTX neuropathy progression relates to tissue regeneration and degeneration, minimally affects the immune system processes, and is heavily sex-dependent at the individual gene level.

neuroscience↗

bioRxiv2023

Sensory innervation of masseter, temporal and lateral pterygoid muscles in common marmosets

Myogenous temporomandibular disorders (TMDM) is associated with an increased responsiveness of nerves innervating the masseter (MM), temporal (TM), medial pterygoid (MPM) and lateral pterygoid muscles (LPM). This study aimed to examine sensory nerve types innervating MM, TM and LPM of adult non-human primate - common marmosets. Sensory nerves are localized in specific regions of these muscles. Pgp9.5, marker for all nerves, and NFH, a marker for A-fibers, showed that masticatory muscles were predominantly innervated with A-fibers. The proportion of C- to A-fibers was highest in LPM, and minimal (6-8%) in MM. All C-fibers (pgp9.5+/NFH-) observed in masticatory muscles were peptidergic (CGRP+) and lacked mrgprD, trpV1 and CHRNA3, a silent nociceptive marker. All fibers in masticatory muscles were labeled with GFAP+, a myelin sheath marker. There were substantially more peptidergic A-fibers (CGRP+/NFH+) in TM and LPM compared to MM. Almost all A-fibers in MM expressed trkC, with some of them having trkB and parvalbumin. In contrast, a lesser number of TM and LPM nerves expressed trkC, and lacked trkB. Tyrosine hydroxylase antibodies, which did not label TG, highlighted sympathetic fibers around blood vessels of the masticatory muscles. Overall, masticatory muscle types of marmosets have distinct and different innervation patterns.

neuroscience↗

bioRxiv2023

Understanding Painful versus Non-Painful Dental Pain in Male and Female Patients: A Transcriptomic Analysis of Human Biopsies

Dental pain from apical periodontitis is an infection induced-orofacial pain condition that presents with diversity in pain phenotypes among patients. While 60% of patients with a full-blown disease present with the hallmark symptom of mechanical allodynia, nearly 40% of patients experience no pain. Furthermore, a sexual dichotomy exists, with females exhibiting lower mechanical thresholds under basal and diseased states. Finally, the prevalence of post-treatment pain refractory to commonly used analgesics ranges from 7-19% (~2 million patients), which warrants a thorough investigation of the cellular changes occurring in different patient cohorts. We, therefore, conducted a transcriptomic assessment of periapical biopsies (peripheral diseased tissue) from patients with persistent apical periodontitis. Surgical biopsies from symptomatic male (SM), asymptomatic male (AM), symptomatic female (SF), and asymptomatic female (AF) patients were collected and processed for bulk RNA sequencing. Using strict selection criteria, our study found several unique differentially regulated genes (DEGs) between symptomatic and asymptomatic patients, as well as novel candidate genes between sexes within the same pain group. Specifically, we found the role of cells of the innate and adaptive immune system in mediating nociception in symptomatic patients and the role of genes involved in tissue homeostasis in potentially inhibiting nociception in asymptomatic patients. Furthermore, sex-related differences appear to be tightly regulated by macrophage activity, its secretome, and/or migration. Collectively, we present, for the first time, a comprehensive assessment of peripherally diseased human tissue after a microbial insult and shed important insights into the regulation of the trigeminal system in female and male patients. SummaryClinical diversity paves the way for translational research. We conducted a comprehensive transcriptomic assessment of peripherally diseased human tissue from patients with apical periodontitis to understand better clinical diversity observed in pain phenotypes between patients as well as perform in-depth analyses of sex-related dimorphism in patients with apical periodontitis.

genomics↗

bioRxiv2021

Mast cell-specific receptor/corticotropin-releasing factor axis regulates alcohol withdrawal-associated headache

Rehabilitation from alcohol addiction or abuse is challenging due to alcohol withdrawal symptoms. Headache is a severe alcohol withdrawal symptom that frequently contributes to rehabilitation failure. Despite the need for treating alcohol withdrawal-induced headache, there is no appropriate therapeutic option available. Development of improved therapeutics will depend on obtaining a clearer understanding of alcohol withdrawal-induced headache pain mechanisms. Here, we show that the mast cell-specific receptor MrgprB2 controls development of alcohol withdrawal-induced headache. Withdrawing alcohol from alcohol-acclimated mice induces strong headache behaviors, including facial allodynia, facial pain expressions, and reduced walking movement, symptoms often observed in humans suffering from headache. Observed pain behaviors were abolished in MrgprB2-deficient mice. We observed in vivo spontaneous activation and hypersensitization of trigeminal ganglia neurons in alcohol withdrawal mice, but not in MrgprB2-deficient mice. Corticotropin-releasing factor (CRF) was increased in dura mater after alcohol withdrawal. Injection of CRF into dura mater resulted in activation of trigeminal ganglia neurons and vasodilation, which was accompanied by headache behavior. In cells, CRF evoked Ca2+ transients via MrgprB2 or human MrgprX2. The results indicate that alcohol withdrawal causes headache via mast cell degranulation in dura mater. The process is under control of MrgprB2/MrgprX2, which would appear to represent a potential target for treating alcohol withdrawal-related headache.

neuroscience↗

bioRxiv2021

Cell division in tissues enables macrophage infiltration

Migration of cells through diverse tissues is essential for development, immune response and cancer metastasis 1-3. To reach their destination, cells must overcome the resistance imposed by complex microenvironments, composed of neighboring cells and extracellular matrix (ECM)4-6. While migration through pores and tracks in ECM has been well studied 4,5,7, little is known about cellular traversal into confining cell-dense tissues. Here by combining quantitative live imaging with genetic and optogenetic perturbations we identify a crucial role for cell division during cell migration into tissues. We find that normal embryonic invasion by Drosophila macrophages between the ectoderm and mesoderm8,9 absolutely requires division of an epithelial ectodermal cell at the site of entry. Dividing ectodermal cells disassemble ECM attachment formed by Integrin-mediated focal adhesions next to mesodermal cells, allowing macrophages to move their nuclei ahead and invade. Decreasing or increasing the frequency of ectodermal division correspondingly either hinders or promotes macrophage invasion. Reducing the levels of focal adhesion components in the ectoderm allows macrophage entry even in the absence of division. Our study demonstrates the critical importance of division at the entry site to enable in vivo cell invasion by relieving the steric impediment caused by focal adhesions. We thus provide a new perspective on the regulation of cellular movement into tissues.

cell biology↗