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.
Cabot
P J
PJ
School of Pharmacy, University of Queensland, St Lucia, Australia.
Cramond
T
T
Smith
M T
MT
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