title: Involvement of the dynorphin/KOR system on the nociceptive, emotional and cognitive manifestations of joint pain in mice.
abstract: Joint pain is a major clinical problem mainly associated to osteoarthritis, and characterized by articular cartilage degradation resulting in a complex chronic pain state that includes nociceptive, emotional and cognitive manifestations. Memory impairment, depressive- and anxiety-like symptoms have been reported to be associated with chronic pain, leading to a decrease of life quality. In this study, we evaluated the involvement of the endogenous dynorphin/kappa opioid receptor (KOR) system on the nociceptive, emotional, cognitive, neurochemical and epigenetic manifestations of joint pain. The murine model of monosodium iodoacetate (MIA) was used to induce joint pain in knockout mice for KOR (KOR-KO), prodynorphin (PDYN-KO) and their wild-type (WT) littermates. KOR-KO and PDYN-KO mice developed mechanical allodynia after intra-articular injection of MIA. This allodynia was significantly increased in both KOR-KO and PDYN-KO when compared to WT mice. Accordingly, both mutants showed increased microglial activation on the lumbar section of the spinal cord after MIA. The emotional responses were evaluated by measuring anxiety-like behaviour in the elevated plus maze and anhedonia as depressive-like behaviour, and cognitive alterations in the object recognition paradigm. Emotional and cognitive impairments after joint pain were differently modified in KOR-KO and PDYN-KO mice. Alterations of corticotropin-releasing factor (CRF) on the amygdala and hippocampus and down regulation of histone 3 acetylation on the amygdala suggest a possible mechanism to explain these emotional and cognitive manifestations. Our results reveal a specific involvement of the dynorphin/KOR system on joint pain manifestations that are usually associated to osteoarthritis.
authors: Laboratory of Neuropharmacology, Department of Experimental and Health Science, Pompeu Fabra University (CEXS-UPF), Barcelona, Spain.
authors: Roger
authors: R
authors: Negrete
authors: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Alicante, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.
authors: María Salud
authors: MS
authors: García Gutiérrez
authors: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Alicante, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.
authors: Jorge
authors: J
authors: Manzanares
authors: Laboratory of Neuropharmacology, Department of Experimental and Health Science, Pompeu Fabra University (CEXS-UPF), Barcelona, Spain. Electronic address: rafael.maldonado@upf.edu.
authors: Rafael
authors: R
authors: Maldonado
mesh_terms: D000107:Acetylation; D000679:Amygdala / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018771:Arthralgia / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D059350:Chronic Pain / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D003071:Cognition / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004195:Disease Models, Animal; D004644:Emotions / Q000502:physiology*; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D004745:Enkephalins; D006657:Histones; D011498:Protein Precursors; D017473:Receptors, Opioid, kappa; D003346:Corticotropin-Releasing Hormone; C033660:preproenkephalin
keywords: Anhedonia; Anxiety; Cognition; Dynorphin; KOR; Opioids; Osteoarthritis