Inhibitory actions of δ₁-, δ₂-, and μ-opioid receptor agonists on excitatory transmission in lamina II neurons of adult rat spinal cord

This study examined the electrophysiological consequences of selective activation of δ₁-, δ₂-, or μ-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 μ receptor agonist [D- Ala², N-MePhe⁴, Gly⁵-ol]enkephalin (DAMGO) or the δ₁ receptor agonist [D-Pen², D-Pen⁵]enkephalin (DPDPE) produced a log-linear, concentration- dependent reduction in the amplitude of the evoked EPSP/EPSC. By comparison, the δ₂ receptor agonist [D-Ala², Glu⁴]deltorphin (DELT) was unable to reduce the evoked EPSP/EPSC by more than 50% at 100 μM, 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)-α-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 δ₂ 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 μM NTB. However, this high concentration of NTB also increased the EC₅₀ of DPDPE by about threefold in a non-competitive manner and antagonized DAMGO in a noncompetitive manner. In contrast, bath application of 33 or 100 nM 7- benzylidenenaltrexone (BNTX), a δ₁ receptor antagonist, produced a concentration-dependent, noncompetitive antagonism of DPDPE, but did not antagonize DELT. A modest noncompetitive antagonism of DAMGO occurred in the presence of 100 nM BNTX. Bath application of 500 nM naloxone competitively antagonized DAMGO as well as DPDPE, increasing their EC₅₀ values by 13.3- and 2.5-fold, respectively. These results provide the first electrophysiological demonstration of functional subtypes of the δ-opioid receptor in rat spinal cord and indicate that activation of either δ₁- or δ₂-opioid receptors inhibits excitatory, glutamatergic afferent transmission in the spinal cord. This effect may mediate the ability of δ₁ or δ₂ receptor agonists to produce antinociception when administered intrathecally in the rat.