Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward

Abstract

Despite the prevalence of opioid misuse, opioids remain the frontline treatment regimen for severe pain. However, opioid safety is hampered by side-effects such as analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, or reward. These side effects promote development of opioid use disorders and ultimately cause overdose deaths due to opioid-induced respiratory depression. The intertwined nature of signaling via μ-opioid receptors (MOR), the primary target of prescription opioids, with signaling pathways responsible for opioid side-effects presents important challenges. Therefore, a critical objective is to uncouple cellular and molecular mechanisms that selectively modulate analgesia from those that mediate side-effects. One such mechanism could be the transactivation of receptor tyrosine kinases (RTKs) via MOR. Notably, MOR-mediated side-effects can be uncoupled from analgesia signaling via targeting RTK family receptors, highlighting physiological relevance of MOR-RTKs crosstalk. This review focuses on the current state of knowledge surrounding the basic pharmacology of RTKs and bidirectional regulation of MOR signaling, as well as how MOR-RTK signaling may modulate undesirable effects of chronic opioid use, including opioid analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, and reward. Further research is needed to better understand RTK-MOR transactivation signaling pathways, and to determine if RTKs are a plausible therapeutic target for mitigating opioid side effects.

Circadian rhythm disruptions associated with opioid use disorder in synaptic proteomes of human dorsolateral prefrontal cortex and nucleus accumbens

“…In addition, PDGFR-B signaling was among the top pathways from altered rhythms in protein expression of DLPFC synaptosomes in OUD. Importantly, PDGF-dependent signaling is involved in numerous opioid actions, including tolerance and reward [ 148 ]. PDGF is a receptor tyrosine kinase, suggesting interactions between tyrosine kinases and opioid receptors may directly modulate glutamate receptor activity [ 149 ] depending on their circadian regulation.…”

Circadian rhythm disruptions associated with opioid use disorder in the synaptic proteomes of the human dorsolateral prefrontal cortex and nucleus accumbens

“…The copyright holder for this preprint (which this version posted April 7, 2023. ; https://doi.org/10.1101/2023.04.07.536056 doi: bioRxiv preprint including tolerance [103,104] and reward [159]. PDGF is a receptor tyrosine kinase, suggesting interactions between tyrosine kinases and opioid receptors may directly modulate glutamate receptor activity [160] depending on their circadian regulation.…”

Single nuclei transcriptomics in human and non-human primate striatum implicates neuronal DNA damage and proinflammatory signaling in opioid use disorder

“…Endothelial cells displayed the second most DEGs behind microglia between unaffected and OUD subjects. Upregulated pathways in endothelial cells included several growth factors, including VEGFR, EGFR, and PDGFR signaling [84][85][86]. These growth factors regulate nociception and opioid tolerance via actions in peripheral circulation and spinal cord 85,87 , suggesting similar pathways in endothelial cells may be involved in alterations associated with OUD in human brain 6 .…”

“…Endothelial cells displayed the second most DEGs in OUD. Upregulated pathways in endothelial cells included several growth factors, VEGFR, EGFR, and PDGFR [104][105][106] (Figure 5C). Several of these growth factors are linked to nociception and opioid tolerance 105,107 .…”