Naloxone, naltrexone and body temperature

Life Sciences, Vol. 40, pp. 1027-1032 Printed in the U.S.A.

Pergamon Journals

NALOXONE. NALTREXONE AND BODY TEMPERATURE R. Eikelboom Department of Psychology Queen's University at Kingston Kingston, Ontario Canada K7L 3N6

(Received in final form December 8, 1986) Summary

The temperature effects of naloxone and naltrexone (l-30 mg/kg) were examined in well habituated male rats. These drugs had a similar time course and potency, producing a dose-dependent hypothermia followed several hours later by a hyperthermia. A subsequent study found that not only did 30 mg/kg of naloxone or naltrexone produce an equivalent hypothermia but this hypothermia was just as pronounced during the dark as in the light part of the cycle. Morphine and opioid peptides have long been known to have pronounced and complex effects on body temperature in rats (1, 2). This suggests a role for the endogenous opioid systems in thermoregulation (3, 4). Blockade of this system by an opioid antagonist might therefore be expected to change body temperature. In previous work it has been shown that the opiate-antagonist naloxone causes a dose-related hypothermia in rats (5-7) and in mice (8). A delayed hyperthermia has also been noted several hours after naloxone was administered (7). Naltrexone, a more potent, and when orally administered, a longer acting, antagonist (9) is also known to have hypothermic effects on body temperature in rats (10) and mice (8). However there have been no comparisons, in rats, of the potency and time course of the effects of these two drugs on body temperature. If other effects are paralleled naltrexone should be more potent and longer lasting in its thermoregulatory effects, a prediction tested in the first study. Naloxone's effects on pain sensitivity are known to show a diurnal rhythm (11). In young rats naloxone is reported to cause a larger reduction in nighttime feeding than in day-time feeding (12). These differences are thought to reflect circadian rhythms in the activity of the endogenous opioid systems. Body temperature is also known to show a circadian rhythm and it is possible that the effects of the opioid antagonists may be different in the day and night. Thus in the second experiment the effects of naloxone and naltrexone on body temperature were compared in the day and night parts of the cycle. Methods Male Wistar rats between 300 and 350 g (Charles River Canada, St. gonstant Quebec) were housed individually in a temperature controlled room (21 + C) with a 12 h L/D cycle. Food and water were available throughout the experiments, which were carried out in the colony room. All animals were well habituated to the housing conditions and experienced extensive handling, rectal temperature 0024-3205/87 $3.00 + .OO Copyright (c) 1987 Pergamon Journals Ltd.

1023

Naloxone, Naltrexone and Temperature

Vol. 40, No. 11, 1937

measurement, and IP saline injections prior to the start of the experiment. Each animal was used only once. Rectal temperatures were measured using a Yellow Springs Telethermometer with a model 423 probe. Animals were intermittently taken from their cage, placed in a small three sided trough, and the rectal probe inserted 6 cm. Temperatures were measured initially at 45 min intervals with the animals being weighed after the first measurement and receiving IP injections after the second measurement. After a number of temperature measurements the interval between measurements was increased to 90 min. For any given measurement the total time from cage opening to cage closing was between one and two minutes. Experiment 1. Dose Response: Animals received injections of either 1, 3, 10 or 30 mg/kg naloxone HCl or naltrexone HCl (n=8) or Saline (2 groups of n=5). Body temperatures were measured both before and at various times after the injection. Experiment 2. Diurnal Rhythm: Animals received injections of saline, 30 mg/kg naloxone or 30 mg/kg naltrexone during either the light (5 hrs after lights on) or dark (2 hrs after lights out) parts of the cycle (n=S). The lights went on at 04:OO h. Temperatures were measured both before and at various times after the injection. Results Experiment 1. Naloxone and naltrexone produced a dose related hypothermia 45 minutes after injection as measured by the change in temperature from time 0 to 45 min after injection (see Figure 1). (Baseline temperatures in the groups did not differ significantly at either time -45 or 0, all p > .20.) A Drug by Dose analysis of variance revealed a significant Dose effect (lJ(4,63)- 5.29, p<.OOl), but no Drug effect or interaction (both F's < 1). Thus naloxone and naltrexone appeared equipotent in terms of their hypothermia-inducing effects. Similar results were found 90 minutes after the injection. Figure 2 shows the time course of this effect for the 30 mg/kg naloxone and naltrexone groups as compared to the saline control group animals and it is evident that the time course of the drugs is similar. At 270 and 360 min after injection a dose related hyperthermia was evident (360 min data shown in Figure 3). Drug by Dose analyses for both these times revealed only a significant Dose effect @(4,63) - 2.9, R<.O5, in both cases). Again it appears that there is little difference in the time course and potency of this effect for naloxone and naltrexone. Experiment 2. Figure 4 shows the effects of naloxone and naltrexone on body temperature during the light and dark parts of the cycle. A Time of Day by Drug analysis of variance was done for each time that temperature was measured. In each case there was a Time of Day main effect (all p<.Ol) reflecting the circadian rhythm in body temperature. At 45 and 90 minutes after drug injection there was a significant Drug effect (F(2,45) = 8.63, p<.OOl, F(2,45) - 3.61, p<.O5, respectively), reflecting the hypothermia of the naloxone and naltrexone group animals. At 270 minutes there was again a significant Drug effect (F(2,45) - 3.80, p<.O5) with the saline group animals having a lower body temperature than animals in the two drug groups. At no time was there a significant Time of Day by Drug group interaction (all F
1029

Naloxone, Naltrexone and Temperature

Vol. 40, No. 11, 1987

0 Saline H Naltrexone A Naloxone

-0.6

-0.8

I

I

3

IO

I -5

DRUG

DOSE

I 30

(mgikg)

F’tr,. 1 Yean (+SEY) chanqe in body temperature over 45 minutes in rats recaivinq an IP InjGtLon of saline or a qiven dose of naloxone or nalttoxone at time 0. 38 .2e--o H H

38. .o-

Saline Naltrexone Naloxone

30mg/kg 30mg/kg

t; eE

37..8-

? I?

37. .6-

nw > w

37 .4-

l37.2-

I

37'.O 2

I

-45

I

I

I

0

45

90

I

180

TIME FI’S.

I

I

270

360

I I

450

(min) ?

Mean body temperature of rats measures before an? after ?n saline, wiloxone or nnltrexone a&ninlstersd at time 0.

TP

injection of

1030

Vol. 40, No. 11, 1987

Naloxone, Naltrexone and Temperature

38.2 I-

38.0 -

1

0 ?/

%

37.8-

5 2

37.6-

E z P

37.4-

UCATION 37.2

Saline 0 n Naltrexone q A Naloxone A 0

37.0 I 4

I

I

I

I

I

3

IO

30

DRUG

DOSE FTC;.

(mg/kg) 3

Mean (f SEW) body temoerature of rats measured 36,Ominutes after an TP injection of saline or a qiven dose of naloxono or naltrexono. Several of these doses were tested in a reolicatlon of this experiment and are shown as open symbols.

DAY 38.8 Saline H Naltrexone 30mg/kg A--A Naloxone30mg/kg 0---O

37.6-

37.2-

$,, -45

, , 0 45 90

I

180

I

270

TIME

t,, -45

, , 0 45 90

I

180

I

270

(min)

FTC,. 4 Mean body temperatures of rats in the day or niqht measured hefore ani after an TP injection of saline, naloxonn or naltrexone admrnistere? at time 0.

Vol. 40, No. 11, 1987

Naloxone, Naltrexone and Temperature

1031

Discussion In their effects on body temperature, naloxone and naltrexone appear to be similar in potency and time course. This contrasts with the results of other comparisons of these drugs where after SC administration naloxone and naltrexone show marked differences in potency (9). There was no evidence in this study of a diurnal rhythm in the effects of these antagonists on body temperature, again in contrast to results in other systems (11, 12). While the highest dose used in the present study was 30 mg/kg other studies show that at higher doses these drugs result in a more pronounced hypothermia (8, 10). It has been suggested that naloxone and naltrexone effects in this dose range reflect action of these drugs at sites other than the opioid receptors (13). The differences between the temperature effects of these drugs and their actions in feeding and pain systems would appear consistent with such an hypothesis. There are, however, several points which suggest caution in this conclusion. First, the temperature effects of these drugs seem to be mediated centrally and are limited to the active isomer (5, 14). Further, while naloxone and naltrexone may have, over the longer term, a different half-life in plasma, initially naltrexone's rate of decline of approximately 18 min (15) is very similar to that of naloxone; approximately, 16 to 24 min (16-18). It is only after this initial decline that naltrexone has a much slower half-life; over 8 hours (14). Finally, the initial effects of naloxone and naltrexone are opposite to the initial effects of a wide range of opioid agonists which at low doses produce, in the rat, a hyperthermia (1, 2), an effect thought to be mediated by an opioid receptor (3, 4). This has led to suggestions that the thermoregulatory effects of naloxone and naltrexone may be mediated by opioid receptors different from the receptors mediating other naloxone effects (5). Clearly resolution of this issue requires further studies. After 4 to 6 hours animals receiving naloxone or naltrexone were hyperthermic relative to animals receiving saline injections. This replicates and extends a previously reported delayed hyperthermia with naloxone (7). From Figure 3 it is evident that this a dose related effect that is similar for naloxone and naltrexone. It should be noted that while this is a hyperthermia relative to saline treated animals, body temperatures do not rise above those evident initially, before injections. These initial temperatures may, however, be elevated due to some residual handling stress.,as temperatures of unstressed animals during the day are usually closer to 37 G. Further work using a temperature telemetry system is planned to address this issue. Explanations of this delayed hyperthermia raise several interesting issues. It is unlikely to be due to a low dose effect of these drugs as animals receiving low doses of naloxone or naltrexone do not, at any time, show a hyperthermia. In fact the effect appears when naloxone should no longer be present in brain or plasma. Since it is, however, evident after naltrexone, which should still be present in brain and plasma (15), this hyperthermia is unlikely to be due to a rebound sensitivity of the receptor. Thornhill, Cooper & Veale (19) tested the acute effects of naloxone and naltrexone in animals just placed in a hot and cold environment and found that the initial drug effect was a hyperthermia in the hot environment and a hypothermia in the cold environment, while after 4 h the drug groups were hyperthermic in both environments. This further supports the suggestion that the delayed hyperthermia is not simply a rebound to the initial drug effect. There is

1032

Naloxone, Naltrexone and Temperature

Vol. 40, No. 11, 1987

preliminary evidence that with repeated naloxone exposure the delayed hyperthegmia becomes more pronounced and can result in temperature elevation of over 1.5 C even with a very small initial hypothermia (Eikelboom, unpublished observations). At present the nature and cause of this delayed hyperthermia seen after injections of these opioid antagonists is unclear. Acknowledgements This research was funded by a grant from the National Science and Engineering Research Council of Canada and by funds from Queen's University. R.E. is a career scientist with the Ontario Ministry of Health. The naloxone and naltrexone were generously supplied by Du Pont through Endo Laboratories Inc. Portions of this paper were presented at the 1985 Society for Neuroscience Meeting. References 1. 2. 3. 4. 5. 6. 7. 8. 9.

10. 11. 12. 13. 14. 15.

W.G. CLARK, Pharmac. Biochem. Behav. lo, 609-613 (1979). W.G. CLARK, Fed. Proc. 3, 2754-2759 (1981). E.B. GELLER, C. HAWK, R.J. TALLARIDA, and M.W. ADLER, Life Sci. 31, 2241-2244 (1982). E.B. GELLER, C. HAWK, S.H. KEINATH, R.J. TALLARIDA, and M.W. ADLER, J. Pharmacol. Exp. Ther. 225, 391-398 (1983). J. BLASIG, V. HOLLT, U. BAUERLE, and A. HERZ, Life Sci. 23, 2525-2532 (1978). J. STEWART, and R. EIKELBOOM, Life Sci. 15, 1165-1172 (1979). R. EIKELBOOM and J. STEWART, Life Sci. 8, 1047-1052 (1981). C.E. ROSOW, J.M. MILLER, J. POULSEN-BURKE, and J. COCHIN, J. Pharmacol. Exp. Ther. 220, 464-467 (1982). H. BLUMBERG, and H.B. DAYTON, Narcotic Antaponists: Advances in Biochemical Psychopharmacology, M.C. Braude, L.S. Harris, E.L. May, J.P. Smith, and J.E. Villarreal, Eds., p. 33-43, Raven, New York, 8 (1974). M. ARY, W. CHESAREK, S.M. SORENSEN, and P. LOMAK, Eur. J. Pharmacol. 2, 215-220 (1976). R.C.A. FREDERICKSON, V. BURGIS, and J.D. EDWARDS, Science 198, 756-758 (1977). M. KAVALIERS, and M. HIRST, Brain Res. 326, 160-167 (1985). J. SAWYNOK, C. PINSKY, and F.S. LABELLA, Life Sci. E. 1621-1632 (1979). Y.-S. PAE, H. IAI, and A. HORITA, Pharmac. Biochen. Behav. 22, 337-339 (1985). A.L. MISRA, R. BLOCH, J. VARDY, J.S. MULE, and K. VEREBELY, Drug Metab. Dispos. ft, 276-280 (1976).

16. A.L. MISRA, R.B. PONTANI, N.L. VADLAMANI, and S.J. MULE, J. Pharmacol. Exp. Ther. 196, 257-268 (1976). 17. R.J. TALLARIDA, C. HARAKAL, J. MASLOW, E.B. GELLER, and M.W. ADLER, J. Pharmacol. Exp. Ther. 206, 38-45 (1978). 18. S.H. WEINSTEIN, M. PFEFFER, and J.M. SCHOR, Narcotic Antagonists: Advances in Biochemical Psychopharmacology M.C. Braude et al., Eds., P 525-535, Even, New York, 8 (1974). lg. J.A. THORNHILL, K.E. COOPER, and W.L. VEALE, J. Pharm. Pharmacol. 22, 427-430 (1980).