Opioid subtype- and cell-type-dependent regulation of inhibitory synaptic transmission in the rat insular cortex

Neuroscience. 2016 Dec 17:339:478-490. doi: 10.1016/j.neuroscience.2016.10.004. Epub 2016 Oct 8.


The insular cortex (IC) plays a principal role in the regulation of pain processing. Although opioidergic agonists depress cortical excitatory synaptic transmission, little is known about opioidergic roles in inhibitory synaptic transmission. In the IC, the opioid receptors differentially regulate the excitatory propagation: agonists of the mu (MOR), delta (DOR), and kappa (KOR) exhibit suppressive, facilitative, and little effects, respectively. Thus, we aimed to examine the effects of opioid receptor agonists on unitary inhibitory postsynaptic currents (uIPSCs) in the IC. Pyramidal and GABAergic neurons in the rat IC were recorded by a multiple whole-cell patch-clamp technique. [D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin acetate salt (DAMGO), an MOR agonist, reduced uIPSC amplitude by 74% in fast-spiking GABAergic interneuron (FS)→FS connections without a significant effect on FS→pyramidal cell (Pyr) connections. These effects of DAMGO were also observed in non-FS→FS and non-FS→Pyr connections: DAMGO reduced the uIPSC amplitude in non-FS→FS but not in non-FS→Pyr connections. DAMGO-induced depression of uIPSCs was blocked by the MOR antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2. The DOR agonist, [D-Pen2,5]-Enkephalin hydrate (DPDPE), reduced uIPSC amplitude by 39% in FS→FS and by 49% in FS→Pyr connections, which was antagonized by the DOR antagonist, naltrindole. However, DPDPE had little effect on non-FS→FS/Pyr connections. (±)-trans-U-50488 methanesulfonate salt (U50488), a KOR agonist, had little effect on uIPSC in FS→FS/Pyr connections. These results suggest that MOR-induced uIPSC depression in FS→FS and non-FS→FS, but not FS→Pyr and non-FS→Pyr connections, results in the depression of excitatory propagation in the IC, which may be an underlying mechanism of the powerful analgesic effects of MOR agonists.

Keywords: GABA; descending inhibition; insular cortex; nociception; opioid receptors.

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Analgesics, Opioid / pharmacology
  • Animals
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • GABAergic Neurons / cytology
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism*
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology*
  • Narcotic Antagonists / pharmacology
  • Neural Pathways / cytology
  • Neural Pathways / drug effects
  • Neural Pathways / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Nociceptive Pain / metabolism
  • Patch-Clamp Techniques
  • Pyramidal Cells / cytology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism*
  • Rats
  • Receptors, Opioid / metabolism*
  • Tissue Culture Techniques


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Receptors, Opioid