PKR activity as an age-dependent developmental regulator of opioid analgesia across distinct inflammatory pain contexts.

• Grant number: 26/02847-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2026
• End date: April 30, 2027
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Guilherme de Araújo Lucas
• Grantee: Emanuela Fuzetti Massaroto
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Opioid analgesia experiences significant changes throughout postnatal development, indicative of structural and functional rearrangement within the nociceptive system and the neuroimmune interface. Despite well-documented age-dependent variations in morphine efficacy and tolerance susceptibility, the molecular processes linking neuronal development, peripheral inflammation, and synaptic plasticity are inadequately understood. The deficiency in understanding is especially significant due to the extensive clinical application of opioids in juvenile populations and the inherent susceptibility of the growing neurological system.The RNA-dependent protein kinase (PKR) serves as a pivotal integrator of these activities. In addition to its established function as an intracellular sensor of double-stranded RNA, PKR serves as a regulator of inflammatory and cellular stress pathways, influencing signaling cascades such as MAPKs (ERK1/2, JNK, and p38), NF-¿B, and eIF2¿. Our initial observations indicate that morphine-induced analgesia is variably regulated across developmental stages and inflammatory conditions, and that pharmacological inhibition of PKR specifically modifies both the intensity and duration of antinociception. These findings substantiate the notion that PKR functions as a central molecular hub, integrating peripheral inflammatory signals and opioid receptor signaling in the dorsal root ganglia.We propose that PKR dynamically modulates the functional relationship between the ¿-opioid receptor (MOR1) and TRPV1 throughout development, influencing phosphorylation states that influence neuronal excitability, inflammatory plasticity, and analgesic efficacy. This regulatory system is anticipated to be dependent on maturation and unique to damage.To evaluate this theory, C57Bl/6 mice at three pivotal developmental phases (P10, P28, and P70) will undergo incisional and thermal inflammatory pain models. The project encompasses: (1) longitudinal behavioral assessments of opioid analgesia and the effects of PKR inhibition; (2) neuroanatomical and cellular mapping of PKR, MOR1, and TRPV1 colocalization in specific dorsal root ganglion neuronal subpopulations (IB4+, IB4¿, and NF200+); and (3) biochemical characterization of PKR, PACT, MAPKs, and eIF2¿ phosphorylation subsequent to injury and morphine administration.This proposal's innovation is the identification of a PKR-MOR1-TRPV1 axis as a key factor in nociceptive plasticity during the maturation of the nervous system. This study aims to redefine the molecular framework of age-dependent analgesia and identify new therapeutic targets for safer and more effective management of inflammatory pain by systematically integrating developmental biology, neuroimmune signaling, and opioid pharmacology. (AU)