The Regulatory Mechanisms and Therapeutic Potential of MicroRNAs: From Chronic Pain to Morphine Tolerance

Abstract

Chronic pain, including cancer-related pain, is a pain condition often caused by inflammation or dysfunctional nerves. Chronic pain treatment poses a significant health care challenge, where opioids especially morphine are widely used and patients often develop tolerance over time with aggravated pain. microRNA (miRNA) is known to play important roles in regulating gene expressions in the nervous system to affect neuronal network plasticity related to algogenesis and the developing of morphine tolerance. In this article, we reviewed studies conducted in rodent animal models investigating the mechanisms of miRNAs regulation in chronic pain with different phenotypes and morphine tolerance. In addition, the potential of targeting miRNAs for chronic pain and morphine tolerance treatment is also reviewed. Finally, we point out the directions of the future research in chronic pain and morphine tolerance.

Keywords: bone cancer pain; chronic pain; microRNA; microglia; morphine tolerance.

Figure 1

A diagrammatic presentation displaying the process from chronic pain to morphine tolerance. Inflammation or nerve injury stimulates the primary afferents of dorsal root ganglion or trigeminal ganglion neurons with an increasing excitability of the neurons. Then the electrical signals are transmitted to the spinal and medullary dorsal horns, where microglial cells are activated. The increasing expression of neurotransmitter receptors and pain pathways in microglia induces chronic pain. And, chronic morphine engagement of μ receptors in the central and peripheral nervous systems mediates morphine tolerance. Microglial cells are activated under the morphine tolerance circumstance, which finally exacerbates chronic pain.

Figure 2

The dysregulation of miRNAs in different regions involved in neuropathic pain and bone cancer pain. In neuropathic pain and bone cancer pain, P2X4 receptors are activated and BDNF is released, which contributes to pain hypersensitivity. Various miRNAs are dysregulated during this process, from DRG to spinal cord and the microglial cells in the dorsal spinal horn.

Figure 3

miRNA mimics and inhibitors administration in different rodent models of pain. Specific miRNAs that are altered in animal models of nociceptive pain [Formalin, complete Freund's adjuvant (CFA) or Carrageenan injection], neuropathic pain [chronic constriction injury (CCI), partial sciatic nerve injury (SNL), spinal cord injury (SCI), spared nerve injury (SNI) or ventral root transection(VRT)] and cancer-related pain [bone cancer pain (BCP)] have been identified as potential therapeutic targets. Schematic indicates that viral vectors [lentivirus (LV), herpes simplex virus (HSV), or adeno-associated virus (AAV)], stabilized locked nucleic acid (LNA) mimics, miRNA agomir or antagomir and anti-miRNA oligonucleotides (AMO) are therapeutic strategies that have been successfully reversed pain phenotypes.

Figure 4

The overlaps between dysregulated miRNAs. The circles include miRNAs that have been mainly implicated in nociceptive pain, neuropathic pain, bone cancer pain, microglia and morphine tolerance. Venn diagram: overlapping regions indicate miRNA intersections (in common) with the reported abnormal states. miRNAs are indicated in black, red, and yellow if dysregulated in one, two, and four states, respectively.