Regulatory mechanisms and therapeutic potential of microglial inhibitors in neuropathic pain and morphine tolerance

Abstract

Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.

Keywords: Microglia; Neuropathic pain (NPP); Morphine tolerance; Microglial inhibitor.

Fig. 1

Roles of microglial inhibitors in the development of NPP and morphine tolerance Activation of microglial receptors leads to activation of numerous intracellular cascades. Microglial inhibitors influence neuropathic pain (NPP) development and morphine tolerance through signaling pathways. The consequence of activation of these cells is the production of nociceptive and antinociceptive factors that are important for the development of pain and morphine tolerance. Microglial cells express a wide spectrum of neurotransmitter receptors (γ-aminobutyric acid (GABA) receptors, adrenoreceptors, dopamine receptors, and purinoreceptors) and receptors for hormones and modulators (histamine, opioids, substance P, neurotrophins, chemokines, interleukins (ILs), and tumor necrosis factor (TNF)-α). Mitogen-activated protein kinases (MAPKs) are crucial players in cell signaling and transmit a broad range of extracellular signals to mediate various intracellular responses that contribute to the development and maintenance of neuropathy. Inhibition of extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation reduces symptoms of NPP, increases opioid effectiveness, and diminishes pain perception. Inhibition of p38 kinase activation reduces symptoms of NPP, but does not change the expression of antinociceptive factors. Other signaling pathways have similar effects. TLR: Toll-like receptor; JNK: c-Jun N-terminal kinase; NF-κB: nuclear factor κB; JAK: Janus kinase