Stimulus frequency and intensity: critical determinants of opioid enhancement or inhibition of evoked methionine-enkephalin release.
Responses to opioids can be bimodal depending on the concentration of opioid used. For example, low concentrations (nM) enhance whereas higher concentrations (10-100 nM) inhibit the electrically evoked release of enkephalin from the myenteric plexus. The nature of the responsiveness of the enkephalin release process to opioids is also dependent on the intracellular and/or extracellular milieu of enkephalin-containing neurons or other neurons of this plexus. Intracellular levels of cAMP, availability of pertussis toxin- and cholera toxin-sensitive guanine nucleotide binding proteins and intracellular calcium concentration have all been shown to be important determinants of opioid excitatory versus inhibitory actions. The present data indicate that the inhibition of enkephalin release produced by U50,488H or sufentanil is no longer observed when the applied voltage is increased 3- or 2-fold, respectively. Under this condition, a previously inhibitory concentration of opioid produces an enhancement of stimulated enkephalin release. Increasing the frequency of the applied stimulation from 5 to 60 Hz (at a constant voltage) also reverses the sufentanil-induced inhibition to a facilitation of enkephalin release. These data indicate that the intensity (voltage) or frequency of the stimulation that is used to release enkephalin is a critical determinant of the nature of its modulation by opioids. The possible relevance of these findings to known differences in opioid sensitivity between different types of pain is discussed.
Sublette
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Department of Biochemistry, State University of New York Health Science Center, Brooklyn 11203.
Gintzler
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AR
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004558:Electric Stimulation; D004744:Enkephalin, Methionine / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D015244:Thiorphan / Q000494:pharmacology
D000700:Analgesics; D004151:Dipeptides; D011480:Protease Inhibitors; D011759:Pyrrolidines; C038361:leucylleucine; D004744:Enkephalin, Methionine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D002216:Captopril; D015244:Thiorphan; D000242:Cyclic AMP; D007930:Leucine; C012211:ubenimex