Deciphering intracellular localization and physiological role of nociceptin and nocistatin

► Nociceptin is a heptadecapeptide located in both the central and peripheral nervous systems. ► It regulates many functions including pain, memory and reproductive behavior. ► The electron microscopy has not been widely used in the intracellular localization of nociceptin. Nociceptin and nocistatin are endogenous ligands of G protein coupled receptor family. Numerous techniques have been used to study the diverse parameters including, localization, distribution and ultrastructure of these peptides. The majority of the study parameters are based on their physiological roles in different organ systems. The present study presents an overview of the different methods used for the study of nociceptin, nocistatin and their receptors. Nociceptin has been implicated in many physiological functions including, nociception, locomotion, stressed-induced analgesia, learning and memory, neurotransmitter and hormone release, renal function, neuronal differentiation, sexual and reproductive behavior, uterine contraction, feeding, anxiety, gastrointestinal motility, cardiovascular function, micturition, cough, hypoxic–ischemic brain injury, diuresis and sodium balance, temperature regulation, vestibular function, and mucosal transport. It has been noted that the use of light and electron microscopy was less frequent, though it may be one of the most promising tools to study the intracellular localization of these neuropeptides. In addition, more studies on the level of circulating nociceptin and nocistatin are also necessary for investigating their clinical roles in health and disease. A variety of modern tools including physiological, light and electron microscopy (EM) are needed to decipher the extent of intracellular localization, tissue distribution and function of these peptides. The intracellular localization of nociceptin and nocistatin will require a high resolution transmission EM capable of identifying these peptides and other supporting molecules that co-localize with them. A tracing technique could also elucidate a possible migratory ability of nociceptin and nocistatin from one cellular compartment to the other.