There has been a great deal of research investigating drug combinations which can increase analgesia. A number of studies have been conducted with one particular combination--opioids combined with the amphetamine drugs. Despite the existing literature, this combination is rarely used in clinical practice. One purpose of this thesis is to review the literature pertaining to the opioid-amphetamine combination. Another purpose of this thesis is to investigate whether dextroamphetamine sulfate ($ circler$Dexedrine) can potentiate morphine sulfate analgesia in rats in the formalin test (Experiment 1). To investigate whether these results can be generalized to another psychostimulant, methylphenidate hydrochloride ($ circler$Ritalin) is used in Experiment 2. Methylphenidate has been chosen instead of another amphetamine drug because it is currently being used in clinical studies without supporting evidence from animal studies. The results of the two experiments indicate that low doses of d-amphetamine and methylphenidate can potentiate the analgesic effects of morphine.

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Thermoregulatory, analgesic and respiratory depressive responses as well as tolerance to morphine were investigated in young (3 to 5 months), mature (10 to 12 month) and senescent (26 to 28 month) male Fischer 344 rats. The thermoregulatory system of senescent rats was not able to maintain body temperature in hot and cold environments as well as the thermoregulatory system of young rats. Additionally, senescent rats had basal rectal temperatures which were approximately one degree lower than basal temperatures in young rats. Subcutaneous morphine caused biphasic effects on body temperature ie. hyperthermia at low doses and hypothermia at high doses. Senescent rats were less responsive to the hypothermic effects of subcutaneous morphine than young rats, but this was not due to decreased subcutaneous blood flow or inability to lose heat. Morphine injections intracerebroventricularly showed no age-related differences. A two site model for the actions of morphine on thermoregulation was proposed and it was suggested that the age-related differences are due to changes in a non periventricular site. Previously reported increased lethality of intravenous morphine in aged rodents was shown to be due to decreased respiratory reserve rather than increased sensitivity to respiratory depression. Senescent rats were also found to acquire tolerance to the thermic effects of morphine less readily than young rats regardless of the route of administration. Normal aging has been characterized as a decrease in adaptability, and it was suggested that senescent rats were less able to compensate for the thermic effects of morphine as well as young rats. In order to determine the mechanisms of decreased adaptability, neurotransmitters proposed to be involved in thermoregulation were injected intracerebroventricularly in morphine tolerant rats. The results suggested a shift from catecholaminergic to cholinergic transmitters with aging.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Analgesias induced by an interaction between restraint and morphine, an interaction between exposure to a novel environment and morphine, and by restraint alone were all shown to be dependent upon an increase in brain tryptophan uptake. Further investigation of the analgesia induced by an interaction between retraint and morphine revealed that the increase in brain tryptophan uptake was induced by sympathetic activity and that the nucleus raphe magnus, the nucleus raphe dorsalis, and the periaqueductal gray were critical to the analgesia. Examination of the endogenous opiod activity critical to analgesia induced by restraint alone revealed that the opioid activity was in the central nervous system and independent of tryptophan uptake. The findings reported in this thesis may be delineating a general mechanism for analgesia that involves stress, serotonin, and opioids.

A series of experiments was carried out to clarify the effects of morphine (0.3 - 10 mg/kg) on intracranial self-stimulation (ICS) and to compare these with the effects of the stimulant amphetamine on this behavior. It was shown that the enhancement of ICS by morphine requires repeated drug exposure, is prevented by pre-exposure to the drug in a non-ICS context, is mimicked by administration of vehicle, and is not reliably reversed by naloxone. In contrast, facilitation of ICS by amphetamine was immediate and remained stable over repeated days of testing. It was concluded that ICS facilitation induced by morphine, but not by amphetamine, is largely the outcome of a learned association between the drug effect and the ICS procedure, and does not appear to be a direct, opiate receptor-mediated effect. Finally, 6-OHDA lesions of ventral tegmental dopamine neurons were shown to block the facilitation of ICS by morphine but not by amphetamine. These lesions were also shown to delay the development of tolerance to morphine-induced catalepsy.

It has been proposed that analgesia in the formalin test is mediated through forebrain systems associated with reinforcement, whereas motor responses necessary for the expression of pain are organized at the level of the brainstem. Because it is located in the brainstem and connected with both limbic reward systems and motor structures, the pedunculopontine tegmental nucleus (PPTg) is a site where reward signals might influence the expression of pain. Experiment 1 confirmed that NMDA-induced lesions of the PPTg block the development of a conditioned place preference to morphine. Subsequently, morphine-induced analgesia was found to be reduced, but not eliminated. The reduction of reward was not significantly correlated with loss of choline acetyltransferase containing neurons in the PPTg. In Experiment 2, PPTg lesions did not affect morphine analgesia in drug naive animals, but produced motor abnormalities and blocked the morphine-induced depression of spontaneous motor activity and catalepsy.

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