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.
Paradoxical, concurrent hyper-and hyporeactivity of a profound nature to specific stimuli occurred when 10 micrograms of morphine was microinjected bilaterally into the periaqueductal gray matter of the rat brain. Both effects at this site were dose-dependent. The hyperreactivity (to previously neutral auditory and visual stimuli) was obtained only with intracerebrally injected morphine and never with intraperitoneally injected morphine or with other opiates administered either way. Rapid tolerance to toxic doses of morphine developed at this site, as well as cross tolerance of the hyporeactivity to painful stimuli between routes (intracerebral to intraperitoneal) of morphine administration. Both the hyper- and hyporeactivity were fully reversible by intracerebral injection of naloxone in the periaqueductal gray. Thus, the periaqueductal gray appears to be a major pathway for morphine action.
Morphine was injected via fine-gauge cannulas permanently implanted in various subcortical sites in the rat brain. In this way the blood-brain barrier was avoided and precise quantities of the drug were delivered to the intended sites. Ten micrograms of morphine in the posterior hypothalamus resulted in significant analgesia, while the same dose injected into the medial septum, the caudate, or the periaqueductal gray matter yielded hyperalgesia. The morphine-produced hyperalgesia at the last-mentioned site was accompanied by stereotyped violent circular leaps, an effect of morphine not previously reported. Thus, intracerebral injections of morphine differ significantly from systemic injections and produce either analgesia or hyperalgesia, depending on site and dose.
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