Role of the sigma-1 receptor in the sensory-discriminative and affective-motivational components of acute and chronic pain

Resumen

Role of the sigma-1 receptor in the sensory-discriminative and affective-motivational components of acute and chronic pain Summary The present Doctoral Thesis focuses on the study of the sigma-1 receptor (σ1R) in the field of pain. This research has been a part of the preclinical σ1R project focusing on drug discovery of σ1R ligands for the treatment of pain at the pharmaceutical company ESTEVE. The overall purpose of this Doctoral Thesis was to explore the role of σ1R in the sensory-discriminative and affective-motivational components of pain. To this end, acetic acid-induced visceral pain and partial sciatic nerve ligation in mice were used to model an acute and chronic pain state, respectively. The sensory discriminative and affective-motivational components of pain in these models were infered by changes in reflexive and non-reflexive behavioural outcomes, respectively. Abdominal contractions (writhing) and paw behavioural hypersensitivity to mechanical and thermal stimuli were analysed as reflexive outcomes. On the other hand, pain-related changes of sweet preference, locomotor activity and reward-seeking behaviour were analysed as non reflexive outcomes. These models and behavioural outcomes were used to evaluate the effect of pharmacological and genetic blockade of σ1R and also the effects of some reference compounds. Furthermore, electrophysiological and molecular studies in knock-out (σ1R /-) mice were used to understand the role of σ1R in the sensory discriminative component of chronic pain. Taken together, the results of this Doctoral Thesis provide new knowledge about σ1R and support the clinical development of selective σ1R antagonists as a suitable therapeutic intervention to treat neuropathic pain and its mood-related comorbidities.