Analgesic and Thermic Responses to Intravenously Administered Morphine in 8- and 24-Week-Old Rats

Abstract

The analgesic and thermic responses to morphine (5 and 10 mg/kg) injected intravenously to 8- and 24-week-old male Sprague-Dawley rats were determined. Greater analgesic and lower hyperthermic responses to morphine in 24-week-old rats in comparison to 8-week-old rats were observed. The pharmacokinetic parameters of morphine administered intravenously were also determined. C_max for 5 and 10 mg/kg doses of morphine were smaller in 24-week-old rats in comparison to 8-week-old rats; however, AUC_0→_∞ was smaller only for 5 mg/kg dose. For 10 mg/kg dose, mean residence time (MRT) and the apparent steady state volume of distribution (V_ss) for the older rats were higher than for the younger ones, but for 5 mg/kg dose the values did not differ. The enhanced responses to morphine in older age group of rats for 5 mg/kg dose cannot be explained solely on the basis of pharmacokinetics. However, for 10 mg/kg dose of morphine, the greater responses in 24-week-old rats could probably be related to increases in MRT and V_ss. Factors other than serum kinetics, like kinetics of morphine in the brain as well as the brain opiate receptors, may also be involved in the differential effects of morphine in rats of different ages.

Time Course of the Distribution of Morphine in Brain Regions, Spinal Cord and Serum following Intravenous Injection to Rats of Differing Ages

“…The pharmacological responses ob served in the present studies are consistent with earlier studies in rats following intraperitoneal [7] and intravenous injection o f mor phine [9] and in postoperative patients [4. 5].…”

“…Previous studies from this laboratory have shown that for a 10 mg/kg dose o f intravenous morphine in the rat, Cmax was lower but the M RT and Vss were significantly higher in 24-week-old than in 8-week-old rats. On the other hand, for a lower dose of morphine (5 mg/kg), the Cmax and AUCo_>oo were lower and the total body clear ance of morphine was higher for older rats than for younger ones [9], Thus, the pharma cokinetic parameters o f morphine in serum o f 8-and 24-week-old rats solely could not ac count for the differential pharmacological re sponses to morphine.…”

“…For the 10 mg/kg dose of morphine, 24-week-old rats had a lower Cmax value but higher MRT and than the 8-week-old rats. The other parameters (AUCo^oo, ti/2, k, Cl,) in the two age groups did not differ [9], Since differential effects o f morphine in rats from two age groups could not be ex plained solely on the basis o f pharmacokinet ics o f morphine in the serum, the present stud ies were undertaken to determine the time course of the distribution o f morphine in sev eral brain regions and spinal cord. The reasons for conducting such studies were based on the fact that morphine-induced analgesia involves both spinal and supraspinal structures and be cause the distribution of morphine is not uni form in brain regions [ …”

“…In a previous study from this laboratory, it was reported that intravenous administration o f morphine (5 or 10 mg/kg) produced a higher level of analgesia but a lower level o f hyperthermia in 24-week-old rats when compared with 8-week-old rats [9], A pharmacokinetic explana tion was sought for the observed effects. Var ious pharmacokinetic parameters o f mor phine were determined in 8-and 24-week-old rats following its intravenous injection.…”

Variation in plasma morphine level and pain sensitivity in prenatally morphinized rats

“…This phenomenon can be attributed to the fact that selection of breeds results in a relative prevalence of K-opioid receptors in breeds 937 and 542, and activation of these receptors may cause hyperalgesia. Age-related peculiarities of the analgetic effect of morphine in rats have also been demonstrated [4]: in 8-week-old animals the effect was reported to be weaker than in 24-week-old ones.…”