Science & Research 49 Volume VIII, 2024, Number 1: MEDICAL BIOLOGY STUDIES, CLINICAL STUDIES, SOCIAL MEDICINE AND HEALTH CARE THE RENIN-ANGIOTENSIN SYSTEM AND ITS INVOLVEMENT IN PAIN CONTROL. A NEW INSIGHT INTO AN OLD SYSTEM Daniela Pechlivanova 1,2*, Dimo Angelov1, Elena Dzhambazova2 1Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria 2Faculty of Medicine, Sofia University “St. Kl. Ohridski” Sofia, Bulgaria Abstract Pain is a symptom usually associated with the development of diseases, but it is always a personal experience influenced by contextual, psychological, and social factors. The processing and interpretation of pain include a complicated brain network consisting variety of subordinated structures. At each level of this neural network, numerous cellular processes contribute to the modulation of pain sensitivity. It has been found that the renin-angiotensin system (RAS) plays a significant role in controlling pain under normal and pathological conditions. Recently, new components of the RAS were discovered characterizing two interacting and balancing arms. The classical arm includes the angiotensin-converting enzyme (ACE), the octapeptide angiotensin II (Ang-II), its primary receptor AT1, and the less common AT2 receptor. The alternative arm includes ACE2, the heptapeptide angiotensin 1-7, and its primary receptor Mas-1. RAS has long been known as a homeostasis system primarily responsible for maintaining the physiological balance between the cardiovascular and renal systems. Accumulating data however enlarged scientific knowledge on the role of RAS in control of brain functions and modulation of pain susceptibility. Scientific evidence indicates a differential involvement of angiotensin receptors in the modulation of pain transmission and suppression. Some data seems contradictory, but a thorough analysis emphasized a specific role of receptor distribution and their selective activation/inhibition on the final effect of pain sensitivity. This review summarizes the available literature on the topic and characterizes some perspectives for further research. Keywords: Renin-angiotensin system, Nociception, ACE2, Ang 1-7 Acknowledgment: This work was financially supported by the Bulgarian National Scientific Fund project КП-06- Н71/9 of the Ministry of Education and Science, Bulgaria. Introduction – pain definition and function Pain is the most common clinical symptom associated with the development of many diseases, in which a part of the somatosensory system is activated. Still, it is always a personal experience influenced by contextual, psychological, and social factors [1,2]. According to the recently revised definition by the International Association for the Study of Pain, pain is accepted as: “An unpleasant sensory and emotional experience associated with, or resembling that associated with actual or potential tissue damage” [3]. In addition, pain can be described in terms of three components - sensory, emotional, and cognitive - reflected in painful stimuli's transmission and modulation mechanisms [4]. The sensory process that conveys noxious signals to the central nervous system (CNS) and triggers pain is known as nociception. Pain usually serves an adaptive role, but may adversely affect social, and psychological well-being. Depending on the duration of the stimulus and plastic changes in the information processing system, acute pain can differ from chronic pain. Acute pain has a protective function detecting harmful stimuli and preventing body damage. Chronic pain, however, persists long after the nociceptive stimulus and activates neuroplasticity processes, leading to the experience of exacerbated responses to both painful (hyperalgesia) and non-painful stimuli (allodynia) [5]. Chronic pain is considered a disease in