Morphine has a dual concentration-dependent effect on K(+)-evoked substance P release from rat peripheral airways.
Our previous investigations of possible lung mechanisms underlying the effectiveness of nebulized morphine for the relief of dyspnoea, have shown a high density of non-conventional opioid binding sites in rat airways with similar binding characteristics (opioid alkaloid-sensitive, opioid peptide-insensitive) to that of putative mu 3-opioid receptors on immune cells. To investigate whether these lung opioid binding sites are functional receptors, this study was designed to determine (using superfusion) whether morphine modulates the K(+)-evoked release of the pro-inflammatory neuropeptide, substance P (SP), from rat peripheral airways. Importantly, K(+)-evoked SP release was Ca(2+)-dependent, consistent with vesicular release. Submicromolar concentrations of morphine (1 and 200 nM) inhibited K(+)-evoked SP release from rat peripheral airways in a naloxone (1 microM) reversible manner. By contrast, 1 microM morphine enhanced K(+)-evoked SP release and this effect was not reversed by 1 microM naloxone. However, 100 microM naloxone not only antagonized the facilitatory effect of 1 microM morphine on K(+)-evoked SP release from rat peripheral airways but it inhibited release to a similar extent as 200 nM morphine. It is possible that these latter effects are mediated by non-conventional opioid receptors located on mast cells, activation of which causes naloxone-reversible histamine release that in turn augments the release of SP from sensory nerve terminals in the peripheral airways. Clearly, further studies are required to investigate this possibility.
School of Pharmacy, University of Queensland, St Lucia, Australia.
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Smith
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D009330:Nebulizers and Vaporizers; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000187:drug effects / Q000378:metabolism*
D009292:Narcotic Antagonists; D009294:Narcotics; D011957:Receptors, Opioid; D013373:Substance P; D009270:Naloxone; D009020:Morphine; D011188:Potassium; D002118:Calcium