Opioid modulation of T-type Ca2+ channel-dependent neuritogenesis/neurite outgrowth through the prostaglandin E2/EP4 receptor/protein kinase A pathway in mouse dorsal root ganglion neurons

Biochem Biophys Res Commun. 2023 Jan 8:639:142-149. doi: 10.1016/j.bbrc.2022.11.108. Epub 2022 Dec 1.

Abstract

Irregular regeneration or inappropriate remodeling of the axons of the primary afferent neurons after peripheral nerve trauma could be associated with the development of neuropathic pain. We analyzed the molecular mechanisms for the neuritogenesis and neurite outgrowth caused by prostaglandin E2 (PGE2) in mouse dorsal root ganglion (DRG) neurons, and evaluated their opioid modulation. PGE2 in combination with IBMX, a phosphodiesterase inhibitor, caused neuritogenesis/neurite outgrowth in DRG cells, an effect abolished by a prostanoid EP4, but not EP2, receptor antagonist, and inhibitors of adenylyl cyclase or protein kinase A (PKA). Blockers of T-type Ca2+ channels (T-channels), that are responsible for window currents involving the sustained low-level Ca2+ entry at voltages near the resting membrane potentials and can be functionally upregulated by PKA, inhibited the neuritogenesis/neurite outgrowth caused by PGE2/IBMX or dibutylyl cyclic AMP, a PKA activator, in DRG neurons, an inhibitory effect mimicked by ZnCl2 and ascorbic acid that block Cav3.2, but not Cav3.1 or Cav3.3, T-channels. Morphine and DAMGO, μ-opioid receptor (MOR) agonists, suppressed the neuritogenesis and/or neurite outgrowth induced by PGE2/IBMX in DRG neurons and also DRG neuron-like ND7/23 cells, an effect reversed by naloxone or β-funaltrexamine, a selective MOR antagonist. Our data suggest that the EP4 receptor/PKA/Cav3.2 pathway is involved in the PGE2-induced neuritogenesis/neurite outgrowth in DRG neurons, which can be suppressed by MOR stimulation. We propose that MOR agonists including morphine in the early phase after peripheral nerve trauma might delay the axonal regeneration of the primary afferent neurons but prevent the development of neuropathic pain.

Keywords: Dorsal root ganglion neuron; Neurite outgrowth; Neuritogenesis; Opioid; Prostaglandin E(2); T-type Ca(2+) channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Analgesics, Opioid* / pharmacology
  • Animals
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dinoprostone / metabolism
  • Ganglia, Spinal / metabolism
  • Mice
  • Morphine / pharmacology
  • Neuralgia* / metabolism
  • Neuronal Outgrowth
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP2 Subtype

Substances

  • 1-Methyl-3-isobutylxanthine
  • Analgesics, Opioid
  • Cyclic AMP-Dependent Protein Kinases
  • Dinoprostone
  • Morphine
  • Ptger4 protein, mouse
  • Receptors, Prostaglandin E, EP2 Subtype