Multiple targets of μ-opioid receptor-mediated presynaptic inhibition at primary afferent Aδ- and C-fibers.

Abstract

Agonists at μ-opioid receptors (MORs) represent the gold standard for the treatment of severe pain. A key element of opioid analgesia is the depression of nociceptive information at the first synaptic relay in spinal pain pathways. The underlying mechanisms are, however, largely unknown. In spinal cord slices with dorsal roots attached prepared from young rats, we determined the inhibitory effect of the selective MOR agonist [d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) on monosynaptic Aδ- and C-fiber-evoked EPSCs in lamina I neurons. DAMGO depressed presynaptically Aδ- and C-fiber-mediated responses, indicating that MORs are expressed on central terminals of both fiber types. We next addressed the mechanisms of presynaptic inhibition. The effect of DAMGO at both Aδ- and C-fiber terminals was mainly mediated by an inhibition of N-type voltage-dependent Ca(2+) channels (VDCCs), and to a lesser extent of P/Q-type VDCCs. Inhibition by DAMGO was not reduced by K(+) channel blockers. The rate of miniature EPSCs was reduced by DAMGO in a dose-dependent manner. The opioid also reduced Ca(2+)-dependent, ionomycin-induced EPSCs downstream of VDCCs. DAMGO had no effect on the kinetics of vesicle exocytosis in C-fiber terminals, but decreased the rate of unloading of Aδ-fiber boutons moderately, as revealed by two-photon imaging of styryl dye destaining. Together, these results suggest that binding of opioids to MORs reduces nociceptive signal transmission at central Aδ- and C-fiber synapses mainly by inhibition of presynaptic N-type VDCCs. P/Q-type VDCCs and the transmitter release machinery are targets of opioid action as well.

• Authors: Bernhard Heinke, Ewald Gingl, Jürgen Sandkühler
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 31 Issue 4 Pg. 1313-22 (Jan 26 2011) ISSN: 1529-2401 [Electronic] United States
• PMID: 21273416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Calcium Channels, N-Type
• Calcium Channels, P-Type
• Calcium Channels, Q-Type
• Receptors, Opioid, mu
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)-

Topics

• Animals
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, N-Type (physiology)
• Calcium Channels, P-Type (physiology)
• Calcium Channels, Q-Type (physiology)
• Electric Stimulation
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)- (pharmacology)
• Excitatory Postsynaptic Potentials
• In Vitro Techniques
• Male
• Miniature Postsynaptic Potentials
• Nerve Fibers, Myelinated (drug effects, physiology)
• Nerve Fibers, Unmyelinated (drug effects, physiology)
• Neural Inhibition
• Neurons, Afferent (drug effects, physiology)
• Patch-Clamp Techniques
• Presynaptic Terminals (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid, mu (agonists, physiology)
• Spinal Cord (drug effects, physiology)
• Spinal Nerve Roots (drug effects, physiology)