Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor

Neuropharmacology. 2017 Sep 1:123:420-432. doi: 10.1016/j.neuropharm.2017.06.019. Epub 2017 Jun 21.

Abstract

The mu and delta opioid receptors (MOR and DOR) are highly homologous members of the opioid family of GPCRs. There is evidence that MOR and DOR interact, however the extent to which these interactions occur in vivo and affect synaptic function is unknown. There are two stable DOR subtypes: DPDPE sensitive (DOR1) and deltorphin II sensitive (DOR2); both agonists are blocked by DOR selective antagonists. Robust motivational effects are produced by local actions of both MOR and DOR ligands in the ventral tegmental area (VTA). Here we demonstrate that a majority of both dopaminergic and non-dopaminergic VTA neurons express combinations of functional DOR1, DOR2, and/or MOR, and that within a single VTA neuron, DOR1, DOR2, and MOR agonists can differentially couple to downstream signaling pathways. As reported for the MOR agonist DAMGO, DPDPE and deltorphin II produced either a predominant K+ dependent hyperpolarization or a Cav2.1 mediated depolarization in different neurons. In some neurons DPDPE and deltorphin II produced opposite responses. Excitation, inhibition, or no effect by DAMGO did not predict the response to DPDPE or deltorphin II, arguing against a MOR-DOR interaction generating DOR subtypes. However, in a subset of VTA neurons the DOR antagonist TIPP-Ψ augmented DAMGO responses; we also observed DPDPE or deltorphin II responses augmented by the MOR selective antagonist CTAP. These findings directly support the existence of two independent, stable forms of the DOR, and show that MOR and DOR can interact in some neurons to alter downstream signaling.

Keywords: Ca(v)2.1; D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) (PubChem CID: 10418702); Delta opioid receptor; H-Tyr-Tic-psi(CH(2)NH)Phe-Phe-OH (TIPP-psi) (PubChem CID: 5311481); Ventral tegmental area; [D-Ala(2), Glu(4)]deltorphin (deltorphin II) (PubChem CID: 123795); [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-Enkephalin acetate salt (DAMGO) (PubChem CID: 5462471); [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) (PubChem CID:104787); mu opioid receptor.

MeSH terms

  • Animals
  • Calcium Channels, N-Type / metabolism
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurotransmitter Agents / pharmacology
  • Patch-Clamp Techniques
  • Potassium Channels / metabolism
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / antagonists & inhibitors
  • Receptors, Opioid, delta / metabolism*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / metabolism*
  • Tissue Culture Techniques
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*

Substances

  • Calcium Channels, N-Type
  • DOR2 protein, rat
  • Neurotransmitter Agents
  • Oprd1 protein, rat
  • Oprm1 protein, rat
  • Potassium Channels
  • RNA, Messenger
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • voltage-dependent calcium channel (P-Q type)