Endogenous Opioids and Their Role in Stem Cell Biology and Tissue Rescue

Abstract

Opioids are considered the oldest drugs known by humans and have been used for sedation and pain relief for several centuries. Nowadays, endogenous opioid peptides are divided into four families: enkephalins, dynorphins, endorphins, and nociceptin/orphanin FQ. They exert their action through the opioid receptors (ORs), transmembrane proteins belonging to the super-family of G-protein-coupled receptors, and are expressed throughout the body; the receptors are the δ opioid receptor (DOR), μ opioid receptor (MOR), κ opioid receptor (KOR), and nociceptin/orphanin FQ receptor (NOP). Endogenous opioids are mainly studied in the central nervous system (CNS), but their role has been investigated in other organs, both in physiological and in pathological conditions. Here, we revise their role in stem cell (SC) biology, since these cells are a subject of great scientific interest due to their peculiar features and their involvement in cell-based therapies in regenerative medicine. In particular, we focus on endogenous opioids' ability to modulate SC proliferation, stress response (to oxidative stress, starvation, or damage following ischemia-reperfusion), and differentiation towards different lineages, such as neurogenesis, vasculogenesis, and cardiogenesis.

Keywords: endogenous opioid peptides; opioid receptors; proliferation; stem cell differentiation; stem cells; stress response.

Figure 1

Schematic representation of human endogenous opioid families and their main functional peptides after precursor processing. For each family of peptides, the following information is reported: (i) the names of the genes (PENK, PDYN, POMC, and PNOC); (ii) the amino acid sequence of the preforms (NCBI Reference Sequence is reported in brackets next to the proform names); (iii) on the right, the names of the main functional peptides highlighted with a corresponding colour in the preform peptide sequence and in the isolated peptide sequence when it is required.

Figure 2

Schematic representation of the opioid receptors’ (MOR, KOR, DOR, and NOP) role in stem cell (SC) proliferation and stress response. Receptor agonists and cell responses written in the figure are obtained from the manuscript information. ”Stem cell” represents all types of SC (or SC-derived progenitors) described in the manuscript. All specifications written under “stress response” indicate the activities investigated in the context of the stress response. Red circle: inhibition; green circle: promotion; yellow circle: not conditioning; MOR: μ opioid receptors; KOR: κ opioid receptors; DOR: δ opioid receptors; NOP: nociception/orphanin FQ receptor; ROS: reactive oxygen species; UPR: unfolded protein response.