Inventi Rapid: Molecular Pharmacology

Inventi:prmp/113437/25

A Review Article of Mechanistic Perspectives on the Molecular Basis of Physical Dependency and Drug Addiction

Opioid receptors represent a crucial class of G-protein coupled receptors [GPCRs] that mediate both the therapeutic and adverse effects of opioids. Since the mid-20th century, research has characterized the major opioid receptor subtypes μ, ẟ, κ and NOP each with distinct endogenous ligands, distribution and roles in analgesia, mood regulation and homeostatic functions. While opioids remain indispensable in clinical pain management, their chronic use is associated with tolerance, physical dependence and addiction. Molecular studies reveal that acute opioid receptor activation suppresses adenylyl cyclase activity, reduces intracellular cAMP, inhibits pre-synaptic calcium ions influx and promotes post synaptic potassium ions efflux, leading to analgesia via neuronal hyperpolarization. However, chronic exposure upregulates the cAMP/PKA pathway, enhances CREB mediated transcription and activates β-arrestin signalling, driving long term neuroadaptations, receptor desensitization and withdrawal syndromes. Importantly, physical dependence reflects adaptive homeostatic changes requiring continuous drug presence, whereas addiction is characterized by compulsive use, dysregulate dopamine signalling and enduring behavioural and psychological changes. These insights not only highlight the complexity of opioid receptor pharmacology but also provide the foundation for developing safer analgesics and therapeutic strategies to dependence and addiction....