Department of Pharmacology of Pain
The Department of Pharmacology of Pain is devoted to studying the initiation and maintenance of pain processes, with particular emphasis on neuropathic pain, which occurs after peripheral nerve injuries due to lesions, cancer, diabetes, multiple sclerosis, hypoxia. This type of pain cannot be relieved by typical painkillers, therefore it is often considered a disorder without prospect of significant improvement. Despite numerous clinical and experimental studies, the molecular mechanisms involved in the development of pain is still not fully understood.
The purpose of our research is to identify alterations in endogenous opioid system homeostasis, which seem to be an important factor in the development of chronic pain. An activation of endogenous analgesic systems in response to the nervous system damage triggers homeostatic mechanisms and in consequence leads to an excessive activity of pro-nociceptive systems. Our research aims to determine various pro-nociceptive peptide pathways which contribute to the development of neuropathy.
Studies using both gene expression profiling and protein analysis indicate that neuropathic pain involves strong activation of many neuronal genes as well as genes related to the immune cell response, including microglial activation. This is an important area of research because there is no data evaluating the efficacy of combined use of opioids and inhibitors of microglia or proinflammatory factors, such as IL-1beta, CCL2, CCL5, as well as blockers of intracellular signaling pathways NF-kB, ERK1/2 and p38MAPK, in the treatment of neuropathic pain. Our studies also involve the search for new targets which could be used to develop more effective treatments of diabetic neuropathy. The results of these experiments demonstrate that modulation of neuroimmunological pathways, by administration of pentoxifylline (an inhibitor of inflammatory cytokines), minocycline (p38MAPK inhibitor), parthenolide (NF-κB inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38MAPK inhibitor) PD98059 (MAPKK inhibitor), attenuates the development of neuropathic pain but may also augment the efficacy of opioids. We hope that the results of our research would provide an experimental basis for future clinical use of combination therapy employing opioid analgesics and glial inhibitors or other substances modulating the synthesis or action of proinflammatory factors, in order to increase the analgesic efficacy of drugs in the treatment of neuropathic pain.
The most important recent scientific discoveries
This paper clarifies attenuated efficacy of opioid drugs in the treatment of neuropathic pain by demonstrating the presence of MOP and KOP receptors and the absence of the opioid DOP receptor on microglial cells. This finding may explain why DOP receptor agonists are inefficient in the treatment of neuropathic pain, as opposed to the attenuated effects of drugs acting through the other two opioid receptors and indicates future directions for the search for novel analgesics.
It has been shown that pro-inflammatory cytokines derived from glial cells activated by the nervous system damage play an important role in the neurotoxic effects of dynorphin in the neuropathic pain model. Inhibition of this activity significantly attenuates adverse effects of dynorphin, which is one of the factors involved in the neuropathic pain development.
Analgesic Properties of Opioid/NK1 Multitarget Ligands with Distinct in Vitro Profiles in Naive and Chronic Constriction Injury Mice.
Joanna Starnowska, Roberto Costante, Karel Guillemyn, Katarzyna Popiolek-Barczyk, Nga N Chung, Carole Lemieux, Attila Keresztes, Joost Van Duppen, Adriano Mollica, John Streicher, Jozef Vanden Broeck, Peter W Schiller, Dirk Tourwé, Joanna Mika, Steven Ballet, Barbara Przewlocka
ACS chemical neuroscience, 10.1021/acschemneuro.7b00226
Bifunctional opioid/nociceptin hybrid KGNOP1 effectively attenuates pain-related behaviour in a rat model of neuropathy.
Joanna Starnowska, Karel Guillemyn, Wioletta Makuch, Joanna Mika, Steven Ballet, Barbara Przewlocka
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, S0928-0987(17)30164-1 10.1016/j.ejps.2017.03.029
Microglial Inhibition Influences XCL1/XCR1 Expression and Causes Analgesic Effects in a Mouse Model of Diabetic Neuropathy.
Magdalena Zychowska, Ewelina Rojewska, Anna Piotrowska, Grzegorz Kreiner, Joanna Mika
Direct and indirect pharmacological modulation of CCL2/CCR2 pathway results in attenuation of neuropathic pain - In vivo and in vitro evidence.
Anna Piotrowska, Klaudia Kwiatkowski, Ewelina Rojewska, Joanna Slusarczyk, Wioletta Makuch, Agnieszka Basta-Kaim, Barbara Przewlocka, Joanna Mika
Journal of neuroimmunology, 10.1016/j.jneuroim.2016.04.017 S0165-5728(16)30095-9
Maraviroc reduces neuropathic pain through polarization of microglia and astroglia - Evidence from in vivo and in vitro studies.
Anna Piotrowska, Klaudia Kwiatkowski, Ewelina Rojewska, Wioletta Makuch, Joanna Mika
Neuropharmacology, 10.1016/j.neuropharm.2016.04.024 S0028-3908(16)30164-2
Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain.
Karel Guillemyn, Joanna Starnowska, Camille Lagard, Jolanta Dyniewicz, Ewelina Rojewska, Joanna Mika, Nga N Chung, Valérie Utard, Piotr Kosson, Andrzej W Lipkowski, Lucie Chevillard, Pol Arranz-Gibert, Meritxell Teixidó, Bruno Megarbane, Dirk Tourwé, Frédéric Simonin, Barbara Przewlocka, Peter W Schiller, Steven Ballet
Journal of medicinal chemistry, 10.1021/acs.jmedchem.5b01976
Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model.
Agnieszka M Jurga, Ewelina Rojewska, Anna Piotrowska, Wioletta Makuch, Dominika Pilat, Barbara Przewlocka, Joanna Mika
Neural plasticity, 10.1155/2016/5238730
Anti-inflammatory properties of tianeptine on lipopolysaccharide-induced changes in microglial cells involve toll-like receptor-related pathways.
Joanna Slusarczyk, Ewa Trojan, Katarzyna Glombik, Anna Piotrowska, Boguslawa Budziszewska, Marta Kubera, Katarzyna Popiolek-Barczyk, Wladyslaw Lason, Joanna Mika, Agnieszka Basta-Kaim
Journal of neurochemistry, 10.1111/jnc.13452
Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine.
Dominika Pilat, Anna Piotrowska, Ewelina Rojewska, Agnieszka Jurga, Joanna Ślusarczyk, Wioletta Makuch, Agnieszka Basta-Kaim, Barbara Przewlocka, Joanna Mika
Molecular and cellular neurosciences, 10.1016/j.mcn.2015.12.013 S1044-7431(15)30053-1
Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.
Ewelina Rojewska, Anna Piotrowska, Wioletta Makuch, Barbara Przewlocka, Joanna Mika
Neuropharmacology, 10.1016/j.neuropharm.2015.10.040 S0028-3908(15)30163-5
Treatment with a carbon monoxide-releasing molecule (CORM-2) inhibits neuropathic pain and enhances opioid effectiveness in rats.
Agnieszka M Jurga, Anna Piotrowska, Joanna Starnowska, Ewelina Rojewska, Wioletta Makuch, Joanna Mika
Pharmacological reports : PR, 10.1016/j.pharep.2015.08.016 S1734-1140(15)00313-8
Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.
Cecilia Betti, Joanna Starnowska, Joanna Mika, Jolanta Dyniewicz, Lukasz Frankiewicz, Alexandre Novoa, Marta Bochynska, Attila Keresztes, Piotr Kosson, Wioletta Makuch, Joost Van Duppen, Nga N Chung, Jozef Vanden Broeck, Andrzej W Lipkowski, Peter W Schiller, Frans Janssens, Marc Ceusters, François Sommen, Theo Meert, Barbara Przewlocka, Dirk Tourwé, Steven Ballet
ACS medicinal chemistry letters, 10.1021/acsmedchemlett.5b00359
IL-1 receptor antagonist improves morphine and buprenorphine efficacy in a rat neuropathic pain model.
Dominika Pilat, Ewelina Rojewska, Agnieszka M Jurga, Anna Piotrowska, Wioletta Makuch, Barbara Przewlocka, Joanna Mika
European journal of pharmacology, 10.1016/j.ejphar.2015.05.058 S0014-2999(15)30056-X
PD98059 Influences Immune Factors and Enhances Opioid Analgesia in Model of Neuropathy.
Ewelina Rojewska, Katarzyna Popiolek-Barczyk, Natalia Kolosowska, Anna Piotrowska, Magdalena Zychowska, Wioletta Makuch, Barbara Przewlocka, Joanna Mika
PloS one, 10.1371/journal.pone.0138583
Beneficial properties of maraviroc on neuropathic pain development and opioid effectiveness in rats.
Klaudia Kwiatkowski, Anna Piotrowska, Ewelina Rojewska, Wioletta Makuch, Agnieszka Jurga, Joanna Slusarczyk, Ewa Trojan, Agnieszka Basta-Kaim, Joanna Mika
Progress in neuro-psychopharmacology & biological psychiatry, 10.1016/j.pnpbp.2015.07.005 S0278-5846(15)30013-0
- ambiguous-cue interpretation
- behavioural analysis
- chronic pain
- G-protein coupled receptors
- gene expression
- hybrid compounds
- immune system
- microglia polarization
- molecular biology
- neuropathic pain
- opioid receptors
- signaling proteins