Inhibitory actions of delta 1-, delta 2-, and mu-opioid receptor agonists on excitatory transmission in lamina II neurons of adult rat spinal cord

Abstract

This study examined the electrophysiological consequences of selective activation of delta 1-, delta 2-, or mu-opioid receptors using whole-cell recordings made from visually identified lamina II neurons in thin transverse slices of young adult rat lumbar spinal cord. Excitatory postsynaptic currents (EPSCs) or potentials (EPSPs) were evoked electrically at the ipsilateral dorsal root entry zone after blocking inhibitory inputs with bicuculline and strychnine, and NMDA receptors with D-2-amino-5-phosphonopentanoic acid. Bath application of the mu receptor agonist [D-Ala2, N-MePhe4, Gly5-ol]enkephalin (DAMGO) or the delta 1 receptor agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) produced a long-linear, concentration-dependent reduction in the amplitude of the evoked EPSP/EPSC. By comparison, the delta 2 receptor agonist [D-Ala2,Glu4]deltorphin (DELT) was unable to reduce the evoked EPSP/EPSC by more than 50% at 100 microM, the highest concentration tested. At concentrations that reduced evoked EPSP/EPSCs by 40-60%, neither DAMGO, DPDPE, nor DELT decreased the amplitude of the postsynaptic current produced by brief pressure ejection of (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, suggesting a presynaptic site of action of these opioid receptor agonists. Bath application of 200 nM naltriben (NTB), a delta 2 receptor antagonist, competitively increased the EC75 of DELT by 15.3-fold, but did not antagonize either DPDPE or DAMGO. The EC75 of DELT was further increased by 169.7-fold in the presence of 1 microM NTB. However, this high concentration of NTB also increased the EC50 of DPDPE by about threefold in a noncompetitive manner and antagonized DAMGO in a noncompetitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Spinal G-Protein-Gated Potassium Channels Contribute in a Dose-Dependent Manner to the Analgesic Effect of μ- and δ- But Not κ-Opioids

“…Indeed, considerable evidence argues that MORand DOR-selective agents inhibit excitatory (glutamatergic) neurotransmitter release by C-fibers in a more potent manner than how they inhibit intrinsic dorsal horn neurons. Specifically, DAMGO, DPDPE, and deltorphin II reduced the amplitude of evoked EPSC/Ps in lamina II neurons at smaller concentrations than those required to blunt the postsynaptic response to AMPA (Glaum et al, 1994;Kohno et al, 1999). Similarly, DAMGO and the endogenous MOR-selective opioid peptides endomorphin I and II suppressed evoked glutamatergic EPSCs at smaller concentrations than those required to evoke significant outward hyperpolarizing inwardly rectifying K ϩ currents in lamina II neurons (Wu et al, 2003).…”

Removing TRPV1-expressing primary afferent neurons potentiates the spinal analgesic effect of δ-opioid agonists on mechano-nociception

“…Spinally administered δ-opioid agonists likely inhibit synaptic transmission through both pre-and postsynaptic mechanisms (Abbadie et al, 2002;Glaum et al, 1994;Kohno et al, 1999;Stewart and Hammond, 1993;Zachariou and Goldstein, 1996). The opioid receptors are coupled to inhibitory G proteins, and voltage-activated Ca 2+ channels are an important downstream signaling target for the opioid analgesic action.…”

“…It has been shown that the release of glutamate and substance P from primary afferent neurons is inhibited by δ-opioid agonists (Glaum et al, 1994;Kohno et al, 1999;Kondo et al, 2005). Thus, the presynaptic action of δ-opioid agonists on nociceptive afferent terminals has been considered an important mechanism underlying the spinal analgesic effect of δ-opioid agonists.…”

“…Intrathecal administration of 5, 10, and 20 µg of the specific δ-opioid receptor agonist DPDPE (Drower et al, 1991;Glaum et al, 1994), dose-dependently increased the paw withdrawal threshold in response to the noxious mechanical stimulus in both vehicle-and RTX-treated rats (Fig. 4).…”

Windup in Dorsal Horn Neurons Is Modulated by Endogenous Spinal μ-Opioid Mechanisms

“…Therefore, facilitated windup could result from an enhanced summation of excitatory synaptic inputs on secondary neurons by lifting the prominent presynaptic inhibition of neurotransmitter release. Because activation of postsynaptic MOR by endogenous opioids leads to membrane hyperpolarization (Yoshimura and North, 1983;Ruda et al, 1984;Glaum et al, 1994), enhanced windup in MOR Ϫ/Ϫ animals may result from the absence of MORs on the somatodendritic region of WDR neurons. However, it is unclear whether endogenous opioids released during 0.2 Hz stimulation are able to induce postsynaptic MOR signaling.…”