Neurobiological Mechanisms Involved in Chronic Pain
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Neurobiological mechanisms involved in chronic pain Roger Negrete Buela DOCTORAL THESIS, 2016 Thesis Director Prof. Rafael Maldonado Departament de Ciències Experimentals i de la Salut Abstract Chronic pain is currently a major clinical issue that represents huge economic and social burdens. Chronic pain treatment currently available presents limited efficacy and significant side effects. One of the reasons for this lack of effective therapeutic approaches is the insufficient knowledge of the mechanisms involved in the development and maintenance of chronic pain and pain-related comorbidities, such as emotional and cognitive manifestations. These associated symptoms negatively affect the life quality of the patients. In our study, we have first validated the different outcomes to measure the nociceptive, emotional and cognitive components of chronic neuropathic pain in mice, and the effects of repeated treatment with pregabalin on these manifestations. We have then identified the influence of different personality traits in the individual variability to chronic neuropathic pain perception in mice, and the emotional and cognitive manifestations associated to this chronic pain using different behavioural, electrophysiological and genetic techniques. The opioid system is a crucial therapeutic target for the treatment of chronic pain, despite the multiple side I effects associated to opioid compounds. Thus, we have evaluated the involvement of specific components of the endogenous opioid system in the behavioural, emotional, cognitive, neurochemical and epigenetic manifestations of chronic osteoarthritis pain in mice. We have identified the endogenous dynorphin / opioid receptor system as an interesting pharmacological target for the treatment of the different manifestations of chronic pain. Resum El dolor crònic és actualment una barrera clínica greu que representa una enorme càrrega econòmica i social. Els tractaments disponibles actualment per al dolor crònic presenten una eficàcia limitada amb considerables efectes adversos. Un dels motius d’aquesta manca d’eficàcia terapèutica recau en l’insuficient coneixement dels mecanismes involucrats en el desenvolupament i el manteniment del dolor crònic i el seus components emocionals i cognitius. Aquests símptomes associats tenen un impacte negatiu en la qualitat de vida dels pacients. En el nostre estudi, primer hem validat les diferents manifestacions nociceptives, emocionals i II cognitives de dolor neuropàtic crònic en ratolins, i els efectes del tractament crònic amb pregabalina en aquestes manifestacions. A continuació, hem identificat la influència dels diferents trets de personalitat en les diferències sobre la percepció del dolor en ratolins, així com les manifestacions emocionals i cognitives del dolor crònic en ratolins mitjançant diferents tècniques comportamentals, electrofisiològiques i genètiques. El sistema opioide representa una diana terapèutica crucial per al tractament del dolor crònic, tot i els seus múltiples efectes adversos associats als compostos opioides. Per això hem avaluat la implicació de components específics del sistema opioide endogen en les manifestacions conductuals, emocionals, cognitives, neuroquímiques i epigenètiques en el dolor osteoartrític crònic en ratolins. Hem identificat el sistema endogen dinorfina/receptor opioide com a una interessant diana farmacològica per al tractament de les diferents manifestacions clíniques del dolor crònic. III IV Abbreviations AC: adenylyl cyclase ATP: adenosine triphosphate ACC: anterior cingulate AMY: amygdala BDNF: brain-derived neurotrophic factor cAMP: cyclic adenosine monophosphate CeA: central nucleus of the amygdala CNS: central nervous system COX: cyclooxygenase CRF: corticotropin-releasing factor DOR: δ (delta) opioid receptor DRG: dorsal root ganglion DSM: Diagnostic and Statistical Manual of Mental Disorders fMRI: functional magnetic resonance imaging FR: fixed ratio GABA: gamma aminobutyric acid Gadd45: growth arrest and DNA damage GPCR: G protein-coupled receptor V H3K9: lysine 9 of histone 3 HIP: hippocampus IASP: International Association for the Study of Pain IC: insular cortex IL: interleukin KO: knockout KOR: κ (kappa) opioid receptor MAP: mitogen-activated protein MIA: monosodium iodoacetate MOR: µ (mu) opioid receptor MRI: magnetic resonance imaging NAc: nucleus accumbens NGF: nerve growth factor NK1: Neurokinin 1 NMDA: N-methyl-D-aspartate NOP: nociceptin / orphanin NR3C1: nuclear receptor subfamily 3, group C, member 1 NSAID: nonsteroidal anti-inflammatory drugs ORL-1: orphanin-receptor like 1 VI PAG: periaqueductal grey PDYN: prodynorphin PENK: proenkephalin PFC: prefrontal cortex POMC: proopiomelanocortin PR: progressive ratio PSNL: partial sciatic nerve ligation PTX: pertussis toxin RVM: rostral ventromedial medulla TLR: toll-like receptor TNFα: tumor necrosis factor α TrkB: tropomyosin receptor kinase B TRP: transient receptor potential TRPV1: transient receptor potential vanilloid type-1 VGCC: voltage gated calcium channel WT: wild type VII VIII IX I NDEX I NDEX Abstract .............................................................................................. I Abbreviations .................................................................................... V Index ................................................................................................. II Introduction ....................................................................................... I 1. Pain: General considerations ........................................................ 3 1.1 A brief history of pain ................................................................. 3 1.2 Definition .................................................................................... 7 1.3 Classification of pain................................................................... 8 a) From acute to chronic pain ................................................... 8 b) Pathophysiological mechanisms of pain ........................... 9 1.4 Physiology of pain: The transmission of the painful stimuli .... 13 1.5 Osteoarthritis pain ................................................................... 25 a) Epidemiology .............................................................................. 25 b) Pathophysiology of osteoarthritis .............................................. 26 i) Peripheral mechanisms ............................................................... 31 ii) Central mechanisms ................................................................... 34 c) Therapeutic approaches for osteoarthritis pain ........................ 36 1.6 Neuropathic pain ...................................................................... 41 I NDEX a) Epidemiology .............................................................................. 41 b) Pathophysiology of neuropathic pain ........................................ 42 i. Peripheral mechanisms ............................................................... 43 ii. Central mechanisms ................................................................... 46 c) Therapeutic approaches for neuropathic pain .......................... 49 1.7 Inter-individual variability in chronic pain ............................... 55 2. Chronic pain manifestations ....................................................... 58 2.1 Emotional manifestations ........................................................ 58 2.2 Cognitive manifestations .......................................................... 61 3. The opioid system ....................................................................... 64 3.1 A brief history of opioids .......................................................... 64 3.2 Endogenous opioid system ...................................................... 67 a. Opioid receptors ......................................................................... 68 b. Endogenous opioid ligands ........................................................ 74 3.3 Enzymes in the catabolism of opioids ...................................... 75 3.4 Endogenous opioid system functions ...................................... 77 a. Endogenous opioid system and pain ......................................... 77 b. Endogenous opioid system and mood disorders ...................... 87 c. Endogenous opioid system and cognition ................................. 92 I NDEX 3.5 The dynorphin/KOR system in chronic pain ............................ 94 a) Dynorphin/KOR system in the nociceptive manifestations of chronic pain .................................................................................... 94 b) Dynorphin/KOR system in emotional manifestations of chronic pain ................................................................................................. 99 c) Dynorphin/KOR system in cognitive manifestations of chronic pain ............................................................................................... 105 3.6 Therapeutic implications of the dynorphin/KOR system ...... 107 Objectives ..................................................................................... 111 Results ........................................................................................... 119 Discussion ..................................................................................... 257 Conclusions ................................................................................... 279 References .................................................................................... 287 Annex ...........................................................................................