Stereospecific and Nonstereospecific Effects of (+)- and (—)-Morphine: Evidence for a New Class of Receptors?

Abstract

The unnatural (+) enantiomer of morphine had minimal activity in three opiate assays in vitro: the rat brain homogenate binding assay, the electrically stimulated guinea pig ileum assay, and the inhibition of adenylate cyclase in neuroblastoma X glioma hybrid cell homogenates. When (+)-morphine was microinfected into the periaqueductal gray (a site known to mediate morphine analgesia) of drug-naive rats, there was only minimal analgesia, but the hyperresponsivity usually observed after microinfection of (-)-morphine occurred. Also, when (+)-morphine was microinfected into the midbrain reticular formation of drug-naive rats, rotation similar to that following microinjection of (-)-morphine occurred. These behaviors were not blocked by naloxone. Significantly, they typically occur in precipitated abstinence in morphine-dependent rats. These observations suggest that there are at least two classes of receptors, one stereospecific and blocked by naloxone and the other only weakly stereospecific and not blocked by naloxone, and that precipitated abstinence may be due, in part, to a selective blockade of receptors of the former class but not of the latter.

Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse

“…(−)-Morphine interacts with µ-opioid receptors to produce potent antinociception and other pharmacological effects. On the other hand, the dextrorotatory (+)-morphine, which is synthesized from sinomenine (Iijima et al, 1978a), does not have any affinity for µ-opioid receptors and therefore does not produce any µ-opioid receptor mediated pharmacological effects (Jacquet et al, 1977). However, we have previously demonstrated that (+)-morphine pretreated spinally attenuates the antinociception produced by spinally-administered (−)-morphine in the mouse.…”

Microglia-Mediated Neurotoxicity Is Inhibited by Morphine through an Opioid Receptor-Independent Reduction of NADPH Oxidase Activity

“…Although the analgesic effect of l-morphine is believed to be mediated through the mu-opioid receptor, whether the effects of the receptor antagonists naloxone and naltrexone are mediated through the mu-opioid receptor remains controversial. Therefore, we used both l-morphine, which has a high affinity to the mu-opioid receptor, and its synthetic enantiomer d-morphine, which does not bind to the mu-opioid receptor (25), to explore the underlying molecular mechanism of the protective effect of morphine on DA neurons in two in vitro models of PD. In this study, we show that subpicomolar concentrations of both lmorphine and d-morphine significantly down-regulate LPS-or 1-methyl-4-phenylpyridinium (MPP ϩ )-induced microglia activation with similar efficacy, clearly showing that the cellular mechanism of morphine-mediated neuroprotection is independent of the mu-opioid receptor pathway.…”

Antianalgesia: Stereoselective Action ofdextro-Morphine overlevo-Morphine on Glia in the Mouse Spinal Cord

“…The synthetic dextro-enantiomer of levo-morphine has minimal activity in the -opioid receptor binding assay, the electrically stimulated guinea pig ileum assay, and the inhibition of adenylate cyclase activity in the neuroblastoma ϫ glioma hybrid cell homogenates, indicating that it does not interact with -opioid receptors (Jacquet et al, 1977). Unlike levo-morphine, which produces potent levo-naloxone reversible analgesia, dextro-morphine microinjected into the periaqueductal gray in rats produces minimal analgesia (Jacquet et al, 1977). In the present study, i.t.…”