Morphine Tolerance, Physical Dependence, and Synthesis of Brain 5-Hydroxytryptamine

Abstract

Tolerance and physical dependence development to morphine in mice can be prevented by concomitant administration of cycloheximide. The fact that the rate of synthesis of brain 5-hydroxytryptamine (5HT) increases with tolerance to morphine suggests that the protein involved may be associated with 5HT synthesis. Inhibition of this synthesis with p-chlorophenylalanine markedly decreases tolerance and physical dependence development to morphine.

Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment

“…A dose of just 3.5 mmol kg À1 of naloxone was sufficient to induce withdrawal jumping symptoms in [Dmt 1 ]DALDAtreated mice, as compared to a dose of 70 mmol kg À1 in morphine-pelleted mice (Hooke et al, 1995). The dose of naloxone needed to precipitate withdrawal is used to estimate the degree of dependence, with higher dependence levels requiring less naloxone (Way et al, 1968;1969). Moreover, in the study by Hooke et al (1995), the animals were made tolerant to morphine by pellet implantation, which results in a greater degree of tolerance than daily injections (Way et al, 1968;1969).…”

“…The dose of naloxone needed to precipitate withdrawal is used to estimate the degree of dependence, with higher dependence levels requiring less naloxone (Way et al, 1968;1969). Moreover, in the study by Hooke et al (1995), the animals were made tolerant to morphine by pellet implantation, which results in a greater degree of tolerance than daily injections (Way et al, 1968;1969). Our results using twice daily injections of [Dmt 1 ]DALDA thus indicate that a very high degree of both tolerance and physical dependence developed to the chronic administration of this drug.…”

“…In the gene expression studies, morphine tolerance was induced by s.c. implantation of one morphine pellet (containing 75 mg morphine free base) for 72 h. This protocol was used because it has been reported to produce a higher degree of tolerance than regular injections (Way et al, 1968;1969). In these studies, we sought to maximize the degree of tolerance to this drug.…”

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

“…There is evidence showing a correlation between the synthesis rate or release of 5-HT in the brain and the development of tolerance, supporting a role of 5-HT in morphine tolerance (14)(15)(16). On the other hand, some studies suggest that 5-HT might not be involved in morphine tolerance (17).…”

Effects of Narcotic Analgesics on Serotonin Metabolism in Brain of Rats and Mice

“…For example, the acute administration of morphine is reported either to produce an increase in cerebral 5-HT turnover in mice (1) and in rats (2, 3), or not to alter the serotonin turnover in mouse brain (4)(5)(6). p-Chlorophenylalanine (p-CPA), a serotonin depletor, is shown either to augment the levorphanol-induced running activity in mice (7), to be ineffective on morphine-stimulated locomotor activity of mice (8) and on levorphanol-induced running activity in mice (9), to reduce the morphine-induced hyperactivity in mice (10), or to reverse the morphine-induced hypoactivity to hyperactivity in rats (6,(11)(12)(13).…”