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Review
. 2020 Mar 4:11:300.
doi: 10.3389/fimmu.2020.00300. eCollection 2020.

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

Halina Machelska  1 , Melih Ö Celik  1
Affiliations
Review

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

Halina Machelska et al. Front Immunol. .

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.

Keywords: analgesia; astrocytes; microglia; nociceptin/orphanin FQ; oligodendrocytes; opioid peptides; opioid receptor signaling; opioid-induced hyperalgesia.

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Figures

Figure 1
Figure 1
Opioid receptors and modulation of pain. (A) Neuronal opioid receptors. Acute activation of Gαi/o-coupled MOP, DOP, KOP, and NOP receptors in central or peripheral sensory neurons leads to the opening of GIRK channels and closing of Cav channels via the Gβγ (path 1). Through the Gβγ, MOP and DOP receptors also open KATP channels (path 2), and MOP receptors close TRPM3 channels (path 3). Through the Gαi/o, MOP receptors inhibit AC, cAMP formation and PKA activity, which leads to closing of TRPV1, HCN, ASIC, and Nav channels (path 4). All these effects decrease neuronal excitability, which results in analgesia. NOP receptors also couple to Gαs, Gαz or Gα16, but their role in pain modulation is unknown (indicated by a question mark). (B) Immune cell opioid receptors. Acute activation of Gαi/o-coupled MOP, DOP, and KOP receptors in immune cells accumulating in peripheral injured tissue leads to the Gβγ-mediated activation of PLC and production of IP3 which activates IP3R in endoplasmic reticulum (ER). This results in the intracellular Ca2+-dependent release of opioid peptides, β-endorphin (END), Met-enkephalin (ENK), and dynorphin A 1-17 (DYN). The secreted opioid peptides activate opioid receptors (MOP, DOP, KOP) in peripheral nerves and diminish pain. NOP receptors are also expressed in immune cells, but their function has not been identified (indicated by a question mark). (C) Microglial opioid receptors. Repetitive activation of MOP receptors in spinal cord microglia upregulates purinergic P2X4 receptors (P2X4R), which triggers the release of BDNF from microglia. The secreted BDNF activates the tropomyosin receptor kinase B (TrkB) to downregulate the K+-Cl− co-transporter KCC2 in GABAergic spinal neurons, which leads to their disinhibition (path 1). Microglial MOP receptor activation can also elevate AA levels to facilitate the opening of BK channels. This triggers the Ca2+ influx via store-operated Ca2+ entry (SOCE) and consequent upregulation of P2X4R and BDNF synthesis in microglia (path 2). Both signaling pathways are suggested to potentiate the neurotransmission in the spinal cord and account for OIH. However, these effects may be a consequence of opioid withdrawal rather than direct hyperalgesic opioid actions. Expression and function of DOP, KOP, and NOP receptors in glia are yet to be clarified.
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