Pharmacological evidence of a possible tryptaminergic regulation of opiate receptors by using indalpine, a selective 5-HT uptake inhibitor

Indalpine or LM 5008 (4-[2-(3-indolyl)ethyl]piperidine), a selective and potent inhibitor of the uptake of 5-hydroxytryptamine, showed analgesic properties in the hot plate test in mice. It enhanced the analgesic effect of morphine and pethidine. This activity could not be explained by alterations of the pharmacokinetics of morphine since the brain morphine level was not changed by pretreatment with indalpine. This drug also antagonized the development of tolerance to morphine in mice. Morphine was 3–7 times more potent in competing for [3H]-naloxone (−NaCl), [3H]-metenkephalin or [3H]-leu-enkephalin binding when animals were pretreated in vivo with indalpine although indalpine itself had no effect on opiate receptor binding sites. In vitro addition of indalpine or 5-HT did not change the activity of morphine on opiate receptor binding sites. In vivo administration of indalpine sensitized the agonist state of opiate receptor binding sites, as measured by [3H]-naloxone (−NaCl) for example, to enkephalin without changing the antagonist state, as measured by [3H]-naloxone (+NaCl). The effect of indalpine was antagonized by the 5-HT synthesis inhibitor PCPA. Moreover, indalpine antagonized the depletion of opioid peptides induced by cyclophosphamide. All these results could suggest a tryptaminergic regulation of opiate receptors.