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, 671 (2), 227-44

The Opioid Peptide Dynorphin Modulates AMPA and Kainate Responses in Acutely Isolated Neurons From the Dorsal Horn

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The Opioid Peptide Dynorphin Modulates AMPA and Kainate Responses in Acutely Isolated Neurons From the Dorsal Horn

M Kolaj et al. Brain Res.

Abstract

In freshly isolated spinal dorsal horn (DH) neurons (laminae I-IV) of the young rat, the effects of dynorphin A1-17, U-50,488H and U-69,593 on inward currents induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) were studied under whole-cell voltage-clamp conditions. When the cells were clamped to a holding potential of -60 mV, co-application of dynorphin A1-17 (10(-6) M) and AMPA (2 x 10(-5) M) reversibly decreased the peak amplitude of the initial transient component of the AMPA-induced current in 72% of the examined cells. In addition, dynorphin (10 microM) in perforated patch-recordings consistently produced a decrease in the steady-state component of the AMPA response. The depressant effect was concentration-dependent (IC50 = 86 nM) and reversible. The dynorphin A1-17-induced depression of the AMPA response was associated with slowing of the response kinetics, including both a 10-90% rise-time and time constant of decay. The AMPA-induced currents were modulated by dynorphin not only during the co-administration but also after the removal of the peptide. Dynorphin increased the initial peak AMPA current in 42% of the examined cells. Similar as with dynorphin A1-17, the peak amplitude of the AMPA-induced current was reversibly suppressed in the presence of 1 microM U-50,488H and U-69,593 in 75% and 86% of the examined cells, respectively. Naloxone and the kappa 1-selective antagonist norbinaltorphimine (nor-BNI) blocked the initial depressant but not late excitatory effects of dynorphin A1-17 and U-50,488H. This antagonistic effect of naloxone and norbinaltorphimine suggests that the depressant effect of dynorphin A1-17 on the AMPA-activated conductance is a true opioid, probably kappa 1-opioid receptor-mediated event. In contrast, the dynorphin-induced late potentiation of AMPA/KA responses appears to be a non-opioid effect since it was not inhibited by nor-BNI, CTAP and naltrindole, the selective kappa-, mu- and delta-opioid receptor blocking agents, respectively. Pretreatment of DH neurons with pertussis toxin blocked the depressant action of dynorphin A1-17, indicating that a Gi- or Go-type G protein was required for this effect on AMPA-activated currents. Intracellular dialysis with a highly specific peptide inhibitor (peptide 6-22) of the cAMP-activated protein kinase (PKA), and with Rp-cAMPS, prevented the depressant effect of dynorphin A1-17. In addition, staurosporine, a nonselective kinase inhibitor, blocked the dynorphin depression of the AMPA response.(ABSTRACT TRUNCATED AT 400 WORDS)

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