A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist

This study used concordant behavioral and electrophysiological approaches t o examine the actions of the prototypic kappa opioid receptor agonist U6959 3 in the rostral ventromedial medulla (RVM). In vitro whole-cell voltage cl amp recordings indicated that bath application of U69593 produced outward c urrents in primary cells in the RVM. In secondary cells, which comprised 80 % of the population, U69593 produced a concentration-dependent and norbinal torphimine (norBNI)-reversible inhibition of evoked excitatory postsynaptic currents (EPSCs) in the absence of any postsynaptic effect. U69593 also de creased the frequency, but not the amplitude of spontaneous miniature excit atory postsynaptic currents (mEPSCs) in secondary cells. The inhibition of excitatory inputs to secondary cells would be consonant with disinhibition of primary cells and the production of antinociception. Consistent with thi s expectation, the activation of kappa opioid receptors in the RVM by micro injection of U69593 produced a dose-dependent increase in paw-withdrawal la tency that was antagonized by norBNI. Furthermore, microinjection of norBNI in the RVM antagonized the increases in paw-withdrawal latency and hot-pla te latency produced by systemically-administered U69593. In contrast, micro injection of norBNI in the RVM did not antagonize the increase in tail-flic k latency produced by systemically-administered U69593. Also, microinjectio n of U69593 in the RVM did not increase tail-flick latency. The highly test -dependent nature of U69593's effects suggests that the mechanisms by which neurons in the RVM modulate thermal nociceptive responses evoked from the tail and hindpaw are not uniform. Collectively, these data suggest that the RVM is a primary site of action for the antinociceptive actions of kappa o pioid receptor agonists and that the mechanism most likely involves a presy naptic inhibition of excitatory inputs to secondary cells. Thus, disinhibit ion of pain inhibitory neurons in the RVM is likely to be a common mechanis m by which opioid receptor agonists produce antinociception, whether by the direct inhibition of inhibitory secondary cells, as in the case of mu opio id receptor agonists, or by a reduction in the excitatory drive to these ne urons, as in the case of kappa opioid receptor agonists. Copyright (C) 2001 International Association for the Study of Pain. Published by Elsevier Sci ence B.V. All rights reserved.