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.

Keywords: mu-opioid receptor; neuropathic pain; opioid signaling; pain; physical dependence; receptor tyrosine kinase; reward; tolerance.

FIGURE 1

Mu-opioid receptor (MOR) signaling transduction pathways, internalization, and recycling. (A) Ligand-activation of MOR activates Gα_i/o-induced inhibition of adenylate cyclase, resulting in decreased intracellular cAMP levels and depleted downstream signaling. Gα_i/o also serves to activate G protein gated inwardly rectifying potassium channels, leading to efflux of potassium ions while βγ heterodimers simultaneously perturb calcium influx by inhibiting voltage gated calcium channels, overall inhibiting intracellular signaling and cellular activity. (B) Ligand-activation of MOR also eventually leads to phosphorylation of MOR c-terminal tail by G protein receptor kinases (GRKs), which enables docking of β-arrestin2 and initiates MOR endocytosis for further receptor degradation or recycling. Note that recruitment of β-arrestin2 can also drive activation of downstream signaling effectors, including ERK, p38 or JNK pathways.

FIGURE 2

Receptor tyrosine kinase (RTK) structure, ligand binding and autophosphorylation, and common downstream signaling pathways. (A) RTK monomers are single transmembrane crossing peptides with extracellular ligand binding sites and tyrosine-rich intracellular effector regions. (B) RTK ligands bind as homo or heterodimers to RTKs inducing trans-autophosphorylation of opposing intracellular tyrosine residues. (C) Ligand-bound RTKs typically recruit protein complexes with SH2 and PTB domains which may activate a number of secondary intracellular messengers known to modulate other transmembrane receptors, intracellular signaling, or transcriptional regulation.

FIGURE 3

Ligand-dependent, ligand-independent, and atypical mechanisms of GPCR modulation of RTKs. (A) Ligand-dependent transactivation: Activated GPCRs induce a variety of downstream signaling pathways including activation of phospho-tyrosine kinases (PTKs), or increase of the influx of Ca²⁺, which activates matrix metalloproteinases (MMP) to cleave cell membrane-bound RTK ligands. (B) Ligand-independent transactivation: Activated GPCRs may also recruit intracellular PTKs to directly phosphorylate tyrosine residues on the intracellular domain of RTKs and induce their activation in a ligand-independent manner. (C) Atypical transactivation: Phox protein complexes activated by GPCRs generate reactive oxygen species which modulate phospho-tyrosine kinases (PTK) and phosphotyrosine phosphatases (PTP) activity to promote phosphorylation of intracellular RTK tyrosine residues. GPCR, G protein coupled receptor; MMP, matrix metalloproteinase; PTK, phosphotyrosine-kinase; PTP, phosphotyrosine phosphatases.

FIGURE 4

Identified mechanisms of MOR-RTK crosstalk. (A) Identified mechanisms of MOR-RTK transactivation: Activated MOR can induce MMP activation via mechanisms including disinhibition Calmodulin (CaM), leading to ligand shedding and ligand-dependent RTK activation. Other ligand-independent mechanisms may involve recruitment of intracellular phosphotyrosine kinases (PTKs) to phosphorylate RTK tyrosine residues. G protein and β-arrestin2 signaling may also be involved in MOR-RTK transactivation. (B) Identified mechanisms of RTK modulation of MOR signaling: Phosphorylated RTK may modulate activation of GPCR via a recruitment of PTKs, or β-arrestins activity. RTK activation may also lead to altered GPCR ligand gene expression or MOR internalization. MOR, mu-opioid receptor; MMP, matrix metalloproteinase; RTK, receptor tyrosine kinase; GPCR, G protein coupled receptor.