A.E. Takemori

The type of analgesic-receptor interaction involved in certain analgesic assays

Abstract The equivalent of p A 2 values were determined for morphine-naloxone in mice using the tail-flick, hot plate and writhing analgesic assays. In spite of marked differences in the ED 50 of morphine among the three assays, the apparent p A 2 values from the three assays were similar which suggests that, in the case of morphine, the three analgesic assays are probably measuring similar analgesic-receptor interactions.

The effect of biogenic amine modifiers on morphine analgesia and its antagonism by naloxone.

The stimulation of dopaminergic receptors, inhibition of serotonin synthesis or blockade of muscarinic receptors by various modifiers led to inhibition of morphine analgesia in mice. Blockade of dopaminergic receptors or the increase in serotonergic or cholinergic activity resulted in the enhancement of morphine analgesia. Serotonergic and cholinergic systems are proposed as positive and the dopaminergic system as negative modulators of morphine analgesia. The modulation of naloxone antagonism was much more complicated than that of morphine analgesia and often the effect of biogenic amine modifiers on antagonism differed from that on analgesia. The fact than biogenic amine modifiers do not affect morphine analgesia and naloxone antagonism by a similar pattern suggests that interaction of narcotics and narcotic antagonists with analgesic receptors may not be exactly the same.

The effect of dopaminergic stimulation and blockade on the nociceptive and antinociceptive responses of mice

Agents which stimulate dopaminergic receptors directly or indirectly such as apomorphine and L-dopa, increased the reactivity of mice to a nociceptive stimulus. The increased reactivity was pharmacologically quantitated by estimating the hyperalgesic ED50 to be 4.4 and 115 mg/kg for apomorphine and L-dopa, respectively. This hyperalgesia was blocked by the dopamine receptor blocking agents, haloperidol and pimozide, but not by the narcotic antagonist, naloxone. Apomorphine antagonizes morphine analgesia. However the induced hyperalgesia only accounts for part of the antagonistic activity of apomorphine. The majority of the antagonistic activity of apomorphine appears to be by means other than action on dopaminergic receptors.

The potentiation of spinal analgesia by leucine enkephalin

In two strains of rats, intrathecal administration of morphine and met-enkephalin was found to produce a dose-dependent analgesic effect as measured by the tail-flick assay. Prior administration of leu-enkelphalin at a dose which had no analgesic effect was found to reduce significantly the analgesic ED50 of both morphine and met-enkephalin. Met-enkephalin pretreatment, at a similar sub-analgesic dose, was without effect. Thus, a differential interaction of the enkephalins with morphine is evident at spinal structures.

Effect of fluoxetine hydrochloride (Lilly 110140), a specific inhibitor of serotonin uptake, on morphine analgesia and the development of tolerance☆

Abstract Fluoxetine, a specific inhibitor of the re-uptake of serotonin in the brain, was found to potentiate the analgesic effect of morphine as measured by the tail-flick method in rats. One dose of fluoxetine thirty minutes prior to analgesic testing in morphine pellet implanted rats was shown to inhibit the analgesic effect of acute challenges of morphine to the same degree as in rats treated daily with fluoxetine during the development of tolerance to morphine. These data indicate that serotonin may play a role in the analgesic effect of morphine, but not in the development of tolerance to narcotic analgesia.

Studies on the quantitative antagonism of analgesics by naloxone and diprenorphine

The equivalents of pA2 values were determined for morphine, pentazocine and etorphine using the antagonists, naloxone and diprenorphine, and the writhing analgesic assay. The apparent pA2 values for pentazocine-naloxone and etorphine-naloxone were significantly lower than that for morphine-naloxone. Similarly, the apparent pA2 value for morphine-diprenorphine was significantly higher than those for pentazocine-diprenorphine and etorphine-diprenorphine. The slopes of the pAX plots of pentazocine and etorphine with both antagonists were greater than unity whereas those of morphine with the antagonists were close to the theoretical slope of -1.0. It is suggested that different analgesics may have different binding functions with the analgesic receptor. The possibility of the existence of different receptors for certain analgesics cannot be excluded.

Differential effects on morphine analgesia and naloxone antagonism by biogenic amine modifiers

Abstract The stimulation of dopaminergic receptors, inhibition of serotonin synthesis or blockade of muscurinic receptors by various modifiers led to inhibition of morphine analgesia in mice. Blockade of dopaminergic receptors or the increase in serotonergic or cholinergic activity resulted in the enhancement of morphine analgesia. Serotonergic and cholinergic systems are proposed as positive and the dopaminergic system as negative modulators of morphine analgesia. The modulation of naloxone antagonism was much more complicated than that of morphine analgesia and often the effect of biogenic amine-modifiers on antagonism differed from that on analgesia. The fact that biogenic amine-modifiers do not affect morphine analgesia and naloxone antagonism by a similar pattern suggest that interaction of narcotics and narcotic antagonists with analgesic receptors may not be exactly the same.

The effect of dopaminergic modifiers on morphine-induced analgesia and respiratory depression.

The influences of the dopaminergic system on morphine-induced analgesia and respiratory depression were compared using modulators of dopaminergic activity. Blockade of dopaminergic receptors by haloperidol or pimozide produced a potentiation of morphine analgesia, while stimulation of dopaminergic activity by L-dopa methyl ester inhibited morphine analgesia. Morphine-induced depression of respiratory rate was potentiated by haloperidol and inhibited by pimozide or L-dopa methyl ester. These results suggest that the dopaminergic system plays a modulating role in morphine-induced analgesia, but not in morphine-induced respiratory depression.

Absorption rates of various substances administered intramuscularly

Abstract The rates of absorption of a variety of compounds from the tibialis anterior muscle of the rat were determined. The substances studied were aqueous solutions of isotopically labeled benzylpenicillin, hexamethonium, glucose, ouabain, urea and water. The disappearance of the radioactivity from muscle was found to be exponential with time and to be described by a single rate constant. The rates were very similar and averaged 0.159/min. The absorption rates of the various substances (molecular weights 20–585) did not appear to vary with their diffusion coefficients but were affected by vasoactive substances. The results suggest that blood flow rather than diffusion is the rate limiting step for absorption from muscle.

Antagonism of morphine-induced behavioral suppression by opiate receptor alkylators

Experiments were conducted to test the in vivo opiate specificity and long-lasting effects of two non-equilibrium opiate antagonists: beta-chlornaltrexamine (beta-CNA) and the beta-fumarate methyl ester derivative of naltrexone (beta-FNA). beta-CNA (2.5 or 5.0 micrograms, ICV) partially antagonized suppression of conditioned autoshaped behavior by morphine, when morphine was administered 48-72 hr after beta-CNA. beta-CNA had no effect on amphetamine-induced suppression of autoshaped responding, nor did it antagonize the suppression in rearing activity induced by either morphine or amphetamine. Similarly, beta-FNA (5 mg/kg, IP) antagonized the suppression of conditioned behavior by morphine, for up to 48 hr, while having no effect on amphetamine-induced suppression of autoshaped responding, or on the suppression of rearing activity induced by morphine or amphetamine. Further peripherally administered beta-FNA acts in the brain, since it antagonized analgesia following ICV morphine administration.