{"id":3698,"date":"2015-12-08T15:24:59","date_gmt":"2015-12-08T14:24:59","guid":{"rendered":"http:\/\/semmelweis.hu\/pharmacology\/?page_id=3698"},"modified":"2025-03-31T12:24:30","modified_gmt":"2025-03-31T10:24:30","slug":"behaviour-and-pain-research-group","status":"publish","type":"page","link":"https:\/\/semmelweis.hu\/pharmacology\/en\/research\/neurotranslation-and-neuromodulation-research-group\/behaviour-and-pain-research-group\/","title":{"rendered":"Behaviour and Pain Research Group"},"content":{"rendered":"<p><iframe loading=\"lazy\" title=\"Translational Neuropharmacology Research Group\" width=\"753\" height=\"424\" src=\"https:\/\/www.youtube.com\/embed\/2nG7bDYVGPU?feature=oembed\" frameborder=\"0\" allow=\"accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share\" referrerpolicy=\"strict-origin-when-cross-origin\" allowfullscreen><\/iframe><\/p>\n<div class=\"responsive-tabs\">\n<h2 class=\"tabtitle\">Projects<\/h2>\n<div class=\"tabcontent\">\n\n<p><strong>Research Group Leader:<\/strong><br \/>\nDr. Mahmoud Al-Khrasani, Associate Professor <a href=\"https:\/\/scholar.google.com\/\">(Google Scholar)<\/a><\/p>\n<p>Our research team at the Department of Pharmacology and Pharmacotherapy continues the Institute\u2019s longstanding tradition of behavioral pharmacological research, focusing on pain and pain management. While pain relief may appear to be a solved issue at first glance, existing medications can be insufficient in certain cases\u2014such as neuropathic pain\u2014and all currently available analgesics have serious side effects. Although behavioral pharmacology might seem outdated, it remains indispensable in psychopharmacology. A recurring challenge in psychopharmacological drug development is that compounds that appear promising and effective in animal models frequently fail during clinical trials, suggesting that current animal models offer limited translational value.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Pain Research Methodology<\/strong><\/p>\n<p>In our pain research, we primarily use <strong>in vivo<\/strong> pain models, supplemented as needed with <strong>ex vivo<\/strong> (isolated organ) and <strong>in vitro<\/strong> (binding assays, immunohistochemistry, PCR, Western blot, etc.) techniques. These latter methods are partly conducted in collaboration with both domestic and international partners (e.g., the Hungarian Academy of Sciences; Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin).<\/p>\n<p>&nbsp;<\/p>\n<p><strong>In Vivo Pain Models<\/strong><\/p>\n<p>Currently, there is no satisfactory way to model pain <strong>in vitro<\/strong>, making <strong>in vivo<\/strong> animal experimentation indispensable for investigating analgesic substances and procedures.<\/p>\n<ul>\n<li><strong>Acute Nociceptive Tests:<\/strong>\n<ul>\n<li>Tail-flick test<\/li>\n<li>Hot-plate test (traditional and ramped-temperature variants)<\/li>\n<\/ul>\n<\/li>\n<li><strong>Inflammatory Models:<\/strong>\n<ul>\n<li><strong>Acute:<\/strong> Formalin test, acetic acid\u2013induced writhing test (duration: 1 hour)<\/li>\n<li><strong>Subacute:<\/strong> Carrageenan-induced inflammatory hyperalgesia (duration: 3\u20135 hours)<\/li>\n<li><strong>Subchronic:<\/strong> Complete Freund\u2019s Adjuvant (CFA)\u2013induced hyperalgesia (duration: 3\u20137 days)<\/li>\n<\/ul>\n<\/li>\n<li><strong>Neuropathic Models:<\/strong>\n<ul>\n<li>Seltzer\u2019s partial ligation of the sciatic nerve, resulting in mononeuropathy (duration: 1\u20133 weeks)<\/li>\n<li>Diabetes-induced polyneuropathy (duration: 6\u201312 weeks)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p><strong>Cognitive Tests<\/strong><\/p>\n<ul>\n<li><strong>5-Choice Serial Reaction Time Task<\/strong> \u2013 attention and impulsivity<\/li>\n<li><strong>Morris Water Maze<\/strong> \u2013 spatial memory<\/li>\n<li><strong>Barnes Maze<\/strong> \u2013 spatial memory<\/li>\n<li><strong>Novel Place Recognition Test<\/strong> \u2013 spatial memory<\/li>\n<li><strong>Spontaneous Alternation<\/strong> \u2013 short-term spatial memory<\/li>\n<li><strong>Cooperative Task in a Skinner Box<\/strong> \u2013 social cognition<\/li>\n<li><strong>Cooperation on a Seesaw<\/strong> \u2013 social cognition<\/li>\n<li><strong>Rescue Box Test<\/strong> \u2013 social cognition<\/li>\n<li><strong>Novel Object Recognition Test<\/strong> \u2013 recognition memory<\/li>\n<li><strong>Fear Conditioning<\/strong> \u2013 fear memory<\/li>\n<li><strong>Passive Avoidance<\/strong> \u2013 fear memory<\/li>\n<li><strong>Shuttle Box<\/strong> \u2013 fear memory<\/li>\n<li><strong>Pot-Jumping<\/strong> \u2013 motor learning<\/li>\n<li><strong>Automated Movement Pattern Analysis in an Open Field<\/strong> \u2013 locomotor activity<\/li>\n<li><strong>Elevated Plus Maze<\/strong> \u2013 anxiety<\/li>\n<li><strong>Conditioned Place Preference<\/strong> \u2013 testing substances with addictive or aversive potential<\/li>\n<li><strong>General, Hypo-, and Hyper-locomotor Activity<\/strong> measurements<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p><strong>Ex Vivo (Isolated Organ) Measurements<\/strong><\/p>\n<p>One classic <strong>ex vivo<\/strong> method for screening opioid analgesics involves experiments on isolated organs. Three tissue types are commonly used:<\/p>\n<ul>\n<li>Mouse vas deferens (containing \u03b4 and \u03bc opioid receptors)<\/li>\n<li>Rat vas deferens (expressing few \u03bc receptors; only highly intrinsic activity ligands are effective)<\/li>\n<li>Guinea pig ileum longitudinal strip (\u03ba and \u03bc receptors)<\/li>\n<\/ul>\n<p>This approach enables cost-effective screening of new (putative) opioid ligands and can also be used to study drug interactions or to model tolerance.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>In Vitro Assays<\/strong><\/p>\n<p>From animals assessed in various pain models, we isolate tissues after the <strong>in vivo<\/strong> measurements to determine receptor density and transmitter levels. We use both quantitative methods (capillary electrophoresis, PCR, Western blot) and semi-quantitative techniques (RNAScope, immunohistochemistry). Depending on the specific research focus, we concentrate primarily on central nervous system regions that are critical for pain transmission.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Ongoing Research Projects<\/strong><\/p>\n<p><strong style=\"font-size: 1rem\">1. Glycine Transporter Inhibitors in Pain and Opioid Analgesic Tolerance<\/strong><\/p>\n<p>Glycine plays a dual role in the central nervous system: it acts as an inhibitory neurotransmitter via its own receptor and also serves as an NMDA receptor co-agonist, thus regulating excitatory neurotransmission. Excessive NMDA receptor activity is a key factor in the development of neuropathic pain and opioid analgesic tolerance. Although NMDA receptor antagonists are effective against neuropathic pain and help reduce opioid tolerance, their side effects (e.g., cognitive dysfunction) limit clinical use. Consequently, alternative strategies for regulating NMDA receptor function are needed. One possibility is to modulate glycine levels by inhibiting its transporters, an approach that may initially boost, then secondarily decrease, receptor activity through desensitization.<\/p>\n<p>Our goal is to investigate how glycine transporter inhibitors affect neuropathic pain and opioid analgesic tolerance. Thus far, our results are promising: in neuropathic pain models, these inhibitors reduced allodynia and mitigated the development of morphine tolerance during chronic treatment.<\/p>\n<p><strong style=\"font-size: 1rem\">2. The Renin\u2013Angiotensin System (RAS) in Pain and Opioid Analgesic Tolerance<\/strong><\/p>\n<p>A growing body of evidence suggests that the renin\u2013angiotensin system (RAS) modulates pain at multiple levels (e.g., dorsal root ganglia, spinal cord). However, the precise mechanisms remain to be clarified. Our group previously demonstrated that antagonists of the angiotensin II type 1 receptor (AT1 receptor)\u2014telmisartan and losartan\u2014can alleviate mononeuropathic pain. We also observed that a subanalgesic dose of telmisartan restored morphine efficacy in neuropathic rats and reduced morphine-induced analgesic tolerance.<\/p>\n<p>We aim to use immunohistochemistry and Western blot to elucidate the mechanism through which AT1 receptor antagonists modulate neuropathic pain and opioid analgesic tolerance. We also plan to investigate their effects on fentanyl-induced analgesic tolerance.<\/p>\n<p><strong style=\"font-size: 1rem\">3. Tolperisone for Neuropathic Pain and Opioid Analgesic Tolerance<\/strong><\/p>\n<p>Tolperisone is a centrally acting muscle relaxant developed in Hungary but relatively lesser-known worldwide. Uniquely among similar drugs, tolperisone does not produce sedative side effects. Although its precise mechanism is not fully understood, it is believed to predominantly act via sodium channel blockade. In recent years, our team, in collaboration with Meditop Zrt., has explored repurposing tolperisone for neuropathic pain. Based on our published animal data, tolperisone shows significant potential both as a standalone therapy and in combination with other neuropathic pain agents.<\/p>\n<p><strong style=\"font-size: 1rem\">4. Kratom: A New Generation of Analgesics<\/strong><\/p>\n<p><em>(Details forthcoming.)<\/em><\/p>\n<p>&nbsp;<\/p>\n<p><strong>Developing a Clinically Relevant, Translational Cognitive Experimental Model<\/strong><\/p>\n<p>Our objective is to create a complex cognitive experimental framework that surpasses currently available methods in predictive value and accuracy when identifying clinically effective cognitive-enhancing mechanisms.<\/p>\n<p>Learning capacity and memory are impaired in various neurological and psychiatric disorders (e.g., Alzheimer\u2019s disease, schizophrenia, autism). Current therapeutic options provide only limited benefit in alleviating these symptoms, underscoring the need for effective cognitive enhancers.<\/p>\n<p>Despite ongoing basic research discovering new cognitive-enhancing mechanisms, the clinical development of such agents has faced near-total attrition over the past decade. This translational gap could be due to inadequate selection of molecular targets and the low predictive value of animal models.<\/p>\n<p>Potential therapeutic targets identified by basic research must be rigorously validated in appropriate animal models to ensure their suitability for pharmaceutical development. However, many existing models yield large numbers of false positives\u2014compounds that appear promising preclinically but show no therapeutic benefit in humans. This shortcoming likely arises from the simplicity of conventional approaches: for instance, impairing a single elementary memory function (e.g., passive avoidance or novel object recognition) with a single dose of a pharmacological agent (e.g., scopolamine) may not accurately reflect the robust cognitive deficits seen in clinical populations. More complex paradigms with greater translational value are needed.<\/p>\n<p>In this project, we train rats and mice in multiple learning paradigms (see the list of methods above). Each task models a distinct human cognitive function typically assessed in clinical practice. Some animals undergo training in several tasks, creating a broad-based \u201cknowledgeable\u201d population.<\/p>\n<p>To test potential cognitive enhancers, animals\u2019 performance is first reduced. The method of impairment is pivotal for modeling the cognitive deficits of a specific disorder. Learning can be impaired pharmacologically (e.g., scopolamine), genetically, by environmental stress, or by selecting inherently poor-learning or aged animals. By applying such interventions, we obtain a \u201cpatient population\u201d of animals with significant cognitive deficits.<\/p>\n<p>Next, we evaluate putative enhancers across a wide range of cognitive functions in these \u201cpatient\u201d animals, employing a methodology analogous to clinical trials: double-blind, placebo-controlled, randomized experiments with (sub)chronic drug administration.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Mechanistic Studies of \u201cEnhancer\u201d Compounds Acting at TAAR Receptors<\/strong><\/p>\n<p>In the early 1960s, Knoll and colleagues developed (-)-deprenyl (selegiline), the first selective monoamine oxidase B (MAO-B) inhibitor, which is widely used in the treatment of Parkinson\u2019s disease, major depression, and as an adjunct therapy in Alzheimer\u2019s disease. Knoll observed that at low doses (-)-deprenyl enhances learning and memory and slows brain aging. He termed this phenomenon the \u201cenhancer effect\u201d (Knoll, 2003). This effect can be induced by (-)-deprenyl\u2014primarily by increasing catecholaminergic tone\u2014or by R-(-)-1-(benzofuran-2yl)-2-propylaminopentane [(-)-BPAP], which boosts both catecholaminergic and serotonergic activity in the CNS.<\/p>\n<p>Enhancer compounds augment stimulus-induced biogenic amine (norepinephrine, dopamine, serotonin) release at very low concentrations, likely through activation of trace amine-associated receptors (TAAR) and by increasing the function of the vesicular monoamine transporter 2 (VMAT2). Our research aims to define the detailed mechanism of this enhancer effect. TAAR receptors may represent a novel therapeutic target for managing neurodegenerative disorders.<\/p>\n<p>In upcoming experiments, we will investigate how different compounds (e.g., TAAR agonists, TAAR antagonists, and both endogenous and synthetic enhancer substances) influence cognitive functions in various behavioral pharmacological tests. Alongside evaluating cognition-enhancing potential, we are also examining whether TAAR-targeting compounds could have analgesic properties, parallel to our ongoing pain-related studies.<\/p>\n\n<\/div><h2 class=\"tabtitle\">Members<\/h2>\n<div class=\"tabcontent\">\n\n<p><strong>Group leader<\/strong>:<\/p>\n<p><a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=1933\">Mahmoud Al-Khrasani<\/a>, (PharmD, PhD, Dr.Habil) Associate Professor<\/p>\n<p><strong>Researcher:<\/strong><\/p>\n<p><a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=10511\">Istv\u00e1n Gyerty\u00e1n<\/a>, (PhD) Senior Researcher\u00a0<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=1944\">Ildik\u00f3 Miklya<\/a>, (PharmD, PhD) Associate Professor\u00a0<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=1941\">P\u00e1l Riba<\/a>, (MD, PhD) Associate Professor<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=1950\">Korn\u00e9l Kir\u00e1ly<\/a>, (MD, PhD) Associate Professor\u00a0<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=10514\">Al\u00edz Ernyey<\/a>, (PhD) University Assistant Professor\u00a0<\/p>\n<p><strong>Scientific advisors:<\/strong><\/p>\n<p><a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=1934\">Zsuzsanna F\u00fcrst<\/a>, (MD, DSc) Emeritus Professor\u00a0<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=1955\">L\u00e1szl\u00f3 G\u00e1bor H\u00e1rsing<\/a>, (MD, DSc) Scientific Advisor\u00a0<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=1943\">J\u00falia Tim\u00e1r<\/a>, (MD, PhD) Associate Professor\u00a0<\/p>\n<p><strong>PhD students<\/strong>:<\/p>\n<p><a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=22521\">Nariman Gomaa Essmat Mohamed Aldeltawab<\/a>, (MSc)<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=22520\">Sarah Abood Kadim Alkafage<\/a>, (MSc)<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=18863\">Anna Galambos<\/a>, (MSc)<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=18886\">Bence Tam\u00e1s Varga<\/a>, (MSc)<br \/>\n<a href=\"https:\/\/semmelweis.hu\/english\/phonebook\/?emp_id=24123\">Imre Boldizs\u00e1r<\/a>, (MD)<br \/>\nYashar Chalabiani, (PharmD)\u00a0<br \/>\nSandra Marouf, (MSc)\u00a0<\/p>\n\n<\/div><h2 class=\"tabtitle\">Gallery<\/h2>\n<div class=\"tabcontent\">\n\n\r\n        [slb_exclude]\r\n        <div class=\"row galeria-wrapper mx-0 h-auto\">\r\n            <div class=\"col-9 pl-0 pr-2\">\r\n            <span class=\"gallery-item frame\">\r\n\t\t\t\t<div class=\"galeria-left-img\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8343-scaled.jpg\"><img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8343-scaled.jpg  \r\n                            alt=\"\" \r\n                            class=\"attachment-sote-gallery-big 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https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8290-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8290-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8290-2048x1365.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8290-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8290-203x135.jpg 203w\" ><\/a><\/div>\r\n                    <\/span>\r\n\r\n                <\/div>\r\n\r\n            <\/div>\r\n\r\n            <span class=\"gallery-item\"><div class=\"hidden\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8298-scaled.jpg\">\r\n        <img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8298-scaled.jpg alt=\"\" class=\"attachment-sote-gallery-big size-sote-gallery-big\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8298-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8298-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8298-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8298-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8298-2048x1365.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8298-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8298-203x135.jpg 203w\" >\r\n        <\/a><\/div><\/span><span class=\"gallery-item\"><div class=\"hidden\"><a href=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8356-scaled.jpg\">\r\n        <img src=https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8356-scaled.jpg alt=\"\" class=\"attachment-sote-gallery-big size-sote-gallery-big\" srcset=\"https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8356-400x267.jpg 400w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8356-1024x683.jpg 1024w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8356-768x512.jpg 768w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8356-1536x1024.jpg 1536w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8356-2048x1365.jpg 2048w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8356-753x502.jpg 753w, https:\/\/semmelweis.hu\/pharmacology\/files\/2024\/08\/BAL8356-203x135.jpg 203w\" >\r\n        <\/a><\/div><\/span>\r\n            <\/div>\r\n\r\n            [\/slb_exclude]\r\n\t\n<\/div><\/div>\n","protected":false},"excerpt":{"rendered":"<p>Research Group Leader: Dr. Mahmoud Al-Khrasani, Associate Professor <a href=\"https:\/\/scholar.google.com\/\">(Google Scholar)<\/a> Our research team at the Department of Pharmacology and Pharmacotherapy continues the Institute\u2019s longstanding tradition of behavioral pharmacological research, focusing on pain and pain management. While pain relief may appear to be a solved issue at first glance, existing medications can be insufficient in certain cases\u2014such as &hellip;<\/p>\n","protected":false},"author":101016,"featured_media":0,"parent":13559,"menu_order":5,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"categories":[],"tags":[],"class_list":["post-3698","page","type-page","status-publish","hentry"],"acf":[],"_links":{"self":[{"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages\/3698","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/users\/101016"}],"replies":[{"embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/comments?post=3698"}],"version-history":[{"count":11,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages\/3698\/revisions"}],"predecessor-version":[{"id":14693,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages\/3698\/revisions\/14693"}],"up":[{"embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/pages\/13559"}],"wp:attachment":[{"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/media?parent=3698"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/categories?post=3698"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/semmelweis.hu\/pharmacology\/wp-json\/wp\/v2\/tags?post=3698"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}