Opioid Receptors in Immune and Glial Cells-Implications for Pain Control.

Halina Machelska,Melih Ö Celik

doi:10.3389/fimmu.2020.00300

Abstract

Opioid receptors comprise μ (MOP), δ (DOP), κ (KOP), and nociceptin/orphanin FQ (NOP) receptors. Opioids are agonists of MOP, DOP, and KOP receptors, whereas nociceptin/orphanin FQ (N/OFQ) is an agonist of NOP receptors. Activation of all four opioid receptors in neurons can induce analgesia in animal models, but the most clinically relevant are MOP receptor agonists (e.g., morphine, fentanyl). Opioids can also affect the function of immune cells, and their actions in relation to immunosuppression and infections have been widely discussed. Here, we analyze the expression and the role of opioid receptors in peripheral immune cells and glia in the modulation of pain. All four opioid receptors have been identified at the mRNA and protein levels in immune cells (lymphocytes, granulocytes, monocytes, macrophages) in humans, rhesus monkeys, rats or mice. Activation of leukocyte MOP, DOP, and KOP receptors was recently reported to attenuate pain after nerve injury in mice. This involved intracellular Ca2+-regulated release of opioid peptides from immune cells, which subsequently activated MOP, DOP, and KOP receptors on peripheral neurons. There is no evidence of pain modulation by leukocyte NOP receptors. More good quality studies are needed to verify the presence of DOP, KOP, and NOP receptors in native glia. Although still questioned, MOP receptors might be expressed in brain or spinal cord microglia and astrocytes in humans, mice, and rats. Morphine acting at spinal cord microglia is often reported to induce hyperalgesia in rodents. However, most studies used animals without pathological pain and/or unconventional paradigms (e.g., high or ultra-low doses, pain assessment after abrupt discontinuation of chronic morphine treatment). Therefore, the opioid-induced hyperalgesia can be viewed in the context of dependence/withdrawal rather than pain management, in line with clinical reports. There is convincing evidence of analgesic effects mediated by immune cell-derived opioid peptides in animal models and in humans. Together, MOP, DOP, and KOP receptors, and opioid peptides in immune cells can ameliorate pathological pain. The relevance of NOP receptors and N/OFQ in leukocytes, and of all opioid receptors, opioid peptides and N/OFQ in native glia for pain control is yet to be clarified.

Highlights

Opioid receptors comprise four members, the classical μ (MOP), δ (DOP), and κ (KOP) receptors, and the nonclassical nociceptin/orphanin FQ (NOP) receptor [reviewed by [1]] (Table 1)
The classical opioid receptors are sensitive to the antagonist naloxone and their endogenous agonists are opioid peptides, such as β-endorphin, enkephalins (Met, Leu-enkephalin), and dynorphins. β-endorphin and enkephalins bind MOP and DOP receptors, whereas dynorphin A 1-17 preferentially acts at KOP receptors
NOP receptors are insensitive to antagonism by naloxone, have low affinity for opioid peptides, and their selective endogenous agonist is nociceptin/orphanin FQ (N/OFQ), which derives from prepro-N/OFQ [(20, 21) reviewed by [6]] (Table 1)

Summary

Introduction

Opioid receptors comprise four members, the classical μ (MOP), δ (DOP), and κ (KOP) receptors, and the nonclassical nociceptin/orphanin FQ (NOP) receptor [reviewed by [1]] (Table 1). All four MOP, DOP, KOP, and NOP receptors have been identified ex vivo at the mRNA and protein levels in various types of immune cells in humans, rhesus monkeys, rats and mice (Table 3).

Results

Conclusion