Sufentanil, Morphine, Met-enkephalin, and k-Agonist (U-50,488H) Inhibit Substance P Release from Primary Sensory Neurons

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Abstract
An in vitro model system for analysis of presynaptic inhibitory actions of spinal opioids has been applied. Embryonic sensory neurons derived from chick dorsal root ganglia were grown in primary cell culture, and the release of substance P was evoked by electrical field stimulation during exposure to drugs with well-demonstrated affinity for opioid receptors. This allowed a pharmacologic characterization of the inhibitory action of specific opioid agonist on the release of substance P as measured by radioimmunoassay (RIA). Sufentanil (0.5 .mu.M), a high affinity .mu. receptor agonist, U-50,488H (25 .mu.M), a selective .kappa. receptor agonist, and morphine (10 .mu.M), an agonist with high affinity for .mu. and .delta. receptors, inhibited the evoked release of substance P by approximately 60%, 40%, and 50%, respectively. For sufentanil the response was demonstrated to be dose-dependent. As is the case for its analgesic action in vivo, morphine was approximately 50-fold less potent than sufentanil on a molar basis in this assay. The actions of sufentanil, U-50-488H and morphine were mimicked by the endogenous opioid peptide met-enkephalin, and its stable synthetic analog D-ala2-met5-enkephalinamide (DAME). Naloxone (25 .mu.M), an opioid receptor antagonist, blocked the inhibitory action of sufentanil (0.5 .mu.M), morphine (5 .mu.M), and DAME (5 .mu.M), but not U-50,488H (10 .mu.M). The action of U-50,488H was partially blocked by the antagonist naltrexone (25 .mu.M). Stereoselectivity of agonist action was confirmed by the failure of dextrorphan (50 .mu.M), an inactive opioid isomer, to inhibit the release of substance P. Actions mediated by specific opioid receptors were thus demonstrated by high affinity responses to agonists, blockade of agonist responses by opioid antagonists, and stereoselectivity. These findings suggest that in the spinal cord presynaptic inhibition of evoked substance P release is mediated by .mu., .kappa. and .delta. opioid receptors located on primary sensory nerve terminals. Activation of these receptors may explain, at least in part, the spinal analgesic actions of specific opioid agonists.

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