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Interaction between veralipride and the endogenous opioid system in the regulation of body temperature in postmenopausal women
Pergamon Journals
Life Sciences, Vol. 42, pp. 547-553 Printed in the U.S.A.
INTERACTION BETWEEN VERALIPRIDE AND THE ENDOGENOUS OPIOID SYSTEM IN THE REGULATION OF BODY TEMPERATURE IhT POSTMENOPAUSAL WOMEN A. Cagnacci,
G.B. Melis,
A.M. Paoletti,
Department of Obstetrics and Gynecology, Roma 67, 56100 Pisa, Italy.
R. Soldani, University
P. Fioretti of Pisa, via
(Received in final form November 30, 1987) Summa9 -The influence of endogenous opioid peptides on body thermoregulation has been studied in untreated postmenopausal women and in the same subjects after chronic administration of the antidopaminergic drug veralipride (200 mg/day for 20 days). Subjects randomly received an infusion of the opioid antagonist naloxone (1.6 mg/h for 4 h) or saline on two consecutive days, both beforc and after veralipride treatment. In untreated subjects body core terrperature, as evaluated by rectal temperature, did not vary during saline infusion, whereas a significant decrease was observed during naloxone infusion. Chronic administration of veralipride significantly increased the hypothermic response to naloxone. Therefore, veralipride seems to increase the activity of endogenous opioid peptides on mechanisms which regulate bcdy temperature in postmenopausal women. In postmenopausal women many neurotransmitter systems involved in thermoregulation seem to be modified by estrogen deficiency (1,2). Among these, reduced activity of the endogenous opioid system seems to exert a key role in the disturbance of mechanisms which regulate thermoregulatory homeostasis (1,3). In fact, postmenopausal vasomotor symptoms have been ascribed to an "endogenou opioid withdrawal syndrome", and it has been hypothesized that the increased activity of the endogenous opioid system represents the common mechanism through which many neuroactive drugs can improve vasomotor symptoms (1,2,5-8). Recently veralipride, a benzamide-derived molecule with antidopaminergic properties (91, has been effectively used in the therapy of postmenopausal vasomotor symptoms (2,10,11). As antidopaminergic drugs enhance the synthesis and secretion of endogenous opioid peptides in both animals and humans (12-151, the present study was undertaken tc 0024-3205/88$3.00 + .OO Copyright (c) 1988 Pergamon Journals Ltd.
548
Veralipride-OpioidsInteractionsin Women
Vol. 42, No. 5, 1988
evaluate whether veralipride can interfere with thermoregulation through an opioid-mediated mechanism in women. With this purpose the thermoregulatory effects of an infusion with the opioid receptor blocking agent naloxone, was evaluated in postmenopausal women before and after the chronic administration of veralipride.
Methods Eight postmenopausal women ageing 48-55 years volounteered for the study. Each had had physiological menopause 2-4 years before the study and were within + 10% of ideal body weight. They had not taken endccrine or neuroactive drugs for at least six months before the study. Subjects were hospitalized in the evening and acclimatized to a room temperature of 20-22 'C on the day before tests. After an overnight fast, at 0800 a.m., an intravenous polyethylene catheter was inserted in an antecubital vein and kept open by a slow infusion of saline solution. At 0900 the saline solution was randomly and in a double blind fashion replaced by a I-hour infusion of naloxone (1.6 mg/h via a peristaltic pump) (16) or by another saline solution. The subjects were supine and were not allowed to eat, drink, smoke or sleep during the period of observation. Core body temperature was measured every 30 minutes by a thermistor probe (YSI 409, Yellow Spring Instruments Co.) inserted 7 cm beyond the anus (17). Temperatures were reported on a card by a nurse. On the next morning, under identical environmental conditions, each subject received the treatment (naloxone or saline) not received the preceeding day. An identical procedure was repeated on two consecutive days at the end of veralipride treatment (100 mg orally, twice daily, for 20 days). Variations of body temperature were evaluated either as absolute values or as net variations from the mean basal preinfusion values. All results are expressed as Mean + SE. Statistical analysis of the results was performed either by Students' "t" test for paired data or by analysis of variance, as appropriate.
Results --Initial core temperatures were not significantly different on each day of observation (Table I). Before treatment with veralipride, saline infusion did not induce any significant change in body temperature (Table I). On the other hand, naloxone infusion significantly reduced body temperature (p
Veralipride-OpioidsInteractionsin Women
Vol. 42, No. 5, 1988
549
TABLE I -Body Core Temperature (Mean + SE) in 8 Postmenopausal Women Before and After Chronic Veralipride Administration (200 n-g/day for 20 days). SALINE before
after
NALOXONE before after
before veralipride
36.70+ 0.05-
36.72+ 0.15-
36.56+a 0.14-
36.36+ 0.15-
after veralipride
36.62+ o.oi-
36.60+ 0.15-
36.60+b 0.11-
36.05+= 0.12-
ap<0.005; CptO.OO1
b
p
vs before
vs after naloxone veralipride
sion (Fig. 1). After 20 days of veralipride administration no significant modification of body temperature was observed during saline infusion (Table I). During naloxone infusion body temperature showed a progressive and significant decrease (p
Discussion It has been previously reported that an endogenous dopaminergic system is involved in control of thermoregulation in animals (9, 17-20). The administration of dopamine and its agonists induces hypothermia which is specifically counteracted by antidopaminergic drugs as haloperidol, pimozide, metoclopramide, sulpiride and veralipride (9,17-20). Administration of antidopaminergic drugs alone does not seem to modify body temperature in animals (17-20). The present study confirms these findings, showing that chronic administration of the antidopaminergic drug veralipride is not able to modify core temperature in postmenopausal women, in spite of its ability to improve postmenopausal hot flushes (2 ,lO, 11). In fact its clinical efficacy suggests that veralipride can interfere with the thermoregulatory mechanisms altered by estrogen deficiency (1,2,10). The experimental demonstration that antidopaminergic drugs enhance endogenous opioid synthesis and secretion (12-15) and the effects of opioid peptides on thermo-
550
Veralipride-OpioidsInteractionsin Women
Vol. 42, No. 5, 1988
INFUSION I
I
CLOCK
HOURS
Fig. 1 Net changes of rectal temperature from mean preinfusion values in 8 postmenopausal women during a 4-h infusion with saline(&-**A) or naloxone (1.6 mg/h;,,). (upper panel) Before veralipride rectal temperature did not vary during saline infusion, while it slowly but significantly (p
Vol. 42, No. 5, 1988
Veralipride-OpioidsInteractionsin Women
551
regulation (21-25) suggest that veralipride can influence thermoregulation through an opioid-mediated mechanism (2). Both opioids and opiates induce varied thermoregulatory modifications in animals (21-27). However the acute administration of low doses of morphine and other mu agonists induces hyperthermia at neutral ambient temperature (20-22 "C)(21-27). Naloxone counteracts this hyperthermia and induces hypothermia when administered alone in the same experimental conditions (21,23,24,28). The present study shows that at a neutral ambient temperature, naloxone induces hypothermia also in postmenopausal women, both in basal conditions and after chronic veralipride administration. Therefore endogenous opioid peptides seem able to affect the mechanisms which regulate thermoregulation in postmenopausal women. Their thermoregulatory activity may be involved, at least in part, in the maintenance of body core temperature in untreated postmenopausal women. In this study the chronic treatment with veralipride increased the endogenous opioid activity on body temperature. In fact,after treatment the hypothermic effect of naloxone was enhanced, suggesting that more endogenous opioid peptides are available in these subjects and may be blocked by naloxone. The enhanced activity of the endogenous opioid system induced by veralipride did not induce hyperthermia in basal conditions. Conversely the administration of both opioids and opiates to animals was shown to be able to increase body temperature (21-27). Different species and different experimental protocols could justify this discrepancy. In addition, interactions with other neurotransmitters known to be involved in the complex mechanisms of thermoregulation (30) can account for the lack of any increase of body basal temperature in postmenopausal women. The enhanced endogenous opioid activity induced by veralipride can account for a greater thermoregulatory stability, as reported in animals (21,251 and therefore for the clinical efficacy of veralipride on postmenopausal hot flushes (2,10,11). Therefore present study suggests that drugs able to improve climacteric vasomotor symptoms can stimulate and probably act through the endogenous opioid system (1,2). The specific site of action of endogenous opioid peptides and their interactions with other neurotransmitters involved in thermoregulation need further elucidations.
Acknowledgments This work was supported by the Consiglio Nazionale delle Ricerthe (C.N.R.) Rome, Italy, grants 86.00531.04 and 86.01787.56. We thank Mr. Gino Narducci, Mr. Silvano Orcesi and Mr. Emilio Madrigali for their technical assistance. Mrs. Gabriella Campani is acknowledged for her excellent secretarial assistance.
552
Veralipride-OpioidsInteractionsin Women
Vol. 42, No. 5, 1988
References ___1 . R.F. CASPER, S.S.C. YEN, Clin. Endocrinol. 22 293-312 (1985). 2 . L. ZICHELLA, P. FALASCHI, P. FIORETTI, G.B.
Vol. 42, No. 5, 1988
Veralipride-OpioidsInteractionsin Women
553
(1977). Sot. Exp. Biol. Med. -.156 523-526 (1979). 1165-1171 28. J. STEWART, R. EIKELBOOM, Life Sciences 25 29. J.W. SIMPKINS, M.J. KATOVICH, 1,.-C. SONGTLife Sciences -32 1957-1966 (1983). 40 2735-2740 (1981). 30. C.M. BLATTEIS, Federation Proc. -
Life Sciences, Vol. 42, pp. 547-553 Printed in the U.S.A.
INTERACTION BETWEEN VERALIPRIDE AND THE ENDOGENOUS OPIOID SYSTEM IN THE REGULATION OF BODY TEMPERATURE IhT POSTMENOPAUSAL WOMEN A. Cagnacci,
G.B. Melis,
A.M. Paoletti,
Department of Obstetrics and Gynecology, Roma 67, 56100 Pisa, Italy.
R. Soldani, University
P. Fioretti of Pisa, via
(Received in final form November 30, 1987) Summa9 -The influence of endogenous opioid peptides on body thermoregulation has been studied in untreated postmenopausal women and in the same subjects after chronic administration of the antidopaminergic drug veralipride (200 mg/day for 20 days). Subjects randomly received an infusion of the opioid antagonist naloxone (1.6 mg/h for 4 h) or saline on two consecutive days, both beforc and after veralipride treatment. In untreated subjects body core terrperature, as evaluated by rectal temperature, did not vary during saline infusion, whereas a significant decrease was observed during naloxone infusion. Chronic administration of veralipride significantly increased the hypothermic response to naloxone. Therefore, veralipride seems to increase the activity of endogenous opioid peptides on mechanisms which regulate bcdy temperature in postmenopausal women. In postmenopausal women many neurotransmitter systems involved in thermoregulation seem to be modified by estrogen deficiency (1,2). Among these, reduced activity of the endogenous opioid system seems to exert a key role in the disturbance of mechanisms which regulate thermoregulatory homeostasis (1,3). In fact, postmenopausal vasomotor symptoms have been ascribed to an "endogenou opioid withdrawal syndrome", and it has been hypothesized that the increased activity of the endogenous opioid system represents the common mechanism through which many neuroactive drugs can improve vasomotor symptoms (1,2,5-8). Recently veralipride, a benzamide-derived molecule with antidopaminergic properties (91, has been effectively used in the therapy of postmenopausal vasomotor symptoms (2,10,11). As antidopaminergic drugs enhance the synthesis and secretion of endogenous opioid peptides in both animals and humans (12-151, the present study was undertaken tc 0024-3205/88$3.00 + .OO Copyright (c) 1988 Pergamon Journals Ltd.
548
Veralipride-OpioidsInteractionsin Women
Vol. 42, No. 5, 1988
evaluate whether veralipride can interfere with thermoregulation through an opioid-mediated mechanism in women. With this purpose the thermoregulatory effects of an infusion with the opioid receptor blocking agent naloxone, was evaluated in postmenopausal women before and after the chronic administration of veralipride.
Methods Eight postmenopausal women ageing 48-55 years volounteered for the study. Each had had physiological menopause 2-4 years before the study and were within + 10% of ideal body weight. They had not taken endccrine or neuroactive drugs for at least six months before the study. Subjects were hospitalized in the evening and acclimatized to a room temperature of 20-22 'C on the day before tests. After an overnight fast, at 0800 a.m., an intravenous polyethylene catheter was inserted in an antecubital vein and kept open by a slow infusion of saline solution. At 0900 the saline solution was randomly and in a double blind fashion replaced by a I-hour infusion of naloxone (1.6 mg/h via a peristaltic pump) (16) or by another saline solution. The subjects were supine and were not allowed to eat, drink, smoke or sleep during the period of observation. Core body temperature was measured every 30 minutes by a thermistor probe (YSI 409, Yellow Spring Instruments Co.) inserted 7 cm beyond the anus (17). Temperatures were reported on a card by a nurse. On the next morning, under identical environmental conditions, each subject received the treatment (naloxone or saline) not received the preceeding day. An identical procedure was repeated on two consecutive days at the end of veralipride treatment (100 mg orally, twice daily, for 20 days). Variations of body temperature were evaluated either as absolute values or as net variations from the mean basal preinfusion values. All results are expressed as Mean + SE. Statistical analysis of the results was performed either by Students' "t" test for paired data or by analysis of variance, as appropriate.
Results --Initial core temperatures were not significantly different on each day of observation (Table I). Before treatment with veralipride, saline infusion did not induce any significant change in body temperature (Table I). On the other hand, naloxone infusion significantly reduced body temperature (p
Veralipride-OpioidsInteractionsin Women
Vol. 42, No. 5, 1988
549
TABLE I -Body Core Temperature (Mean + SE) in 8 Postmenopausal Women Before and After Chronic Veralipride Administration (200 n-g/day for 20 days). SALINE before
after
NALOXONE before after
before veralipride
36.70+ 0.05-
36.72+ 0.15-
36.56+a 0.14-
36.36+ 0.15-
after veralipride
36.62+ o.oi-
36.60+ 0.15-
36.60+b 0.11-
36.05+= 0.12-
ap<0.005; CptO.OO1
b
p
vs before
vs after naloxone veralipride
sion (Fig. 1). After 20 days of veralipride administration no significant modification of body temperature was observed during saline infusion (Table I). During naloxone infusion body temperature showed a progressive and significant decrease (p
Discussion It has been previously reported that an endogenous dopaminergic system is involved in control of thermoregulation in animals (9, 17-20). The administration of dopamine and its agonists induces hypothermia which is specifically counteracted by antidopaminergic drugs as haloperidol, pimozide, metoclopramide, sulpiride and veralipride (9,17-20). Administration of antidopaminergic drugs alone does not seem to modify body temperature in animals (17-20). The present study confirms these findings, showing that chronic administration of the antidopaminergic drug veralipride is not able to modify core temperature in postmenopausal women, in spite of its ability to improve postmenopausal hot flushes (2 ,lO, 11). In fact its clinical efficacy suggests that veralipride can interfere with the thermoregulatory mechanisms altered by estrogen deficiency (1,2,10). The experimental demonstration that antidopaminergic drugs enhance endogenous opioid synthesis and secretion (12-15) and the effects of opioid peptides on thermo-
550
Veralipride-OpioidsInteractionsin Women
Vol. 42, No. 5, 1988
INFUSION I
I
CLOCK
HOURS
Fig. 1 Net changes of rectal temperature from mean preinfusion values in 8 postmenopausal women during a 4-h infusion with saline(&-**A) or naloxone (1.6 mg/h;,,). (upper panel) Before veralipride rectal temperature did not vary during saline infusion, while it slowly but significantly (p
Vol. 42, No. 5, 1988
Veralipride-OpioidsInteractionsin Women
551
regulation (21-25) suggest that veralipride can influence thermoregulation through an opioid-mediated mechanism (2). Both opioids and opiates induce varied thermoregulatory modifications in animals (21-27). However the acute administration of low doses of morphine and other mu agonists induces hyperthermia at neutral ambient temperature (20-22 "C)(21-27). Naloxone counteracts this hyperthermia and induces hypothermia when administered alone in the same experimental conditions (21,23,24,28). The present study shows that at a neutral ambient temperature, naloxone induces hypothermia also in postmenopausal women, both in basal conditions and after chronic veralipride administration. Therefore endogenous opioid peptides seem able to affect the mechanisms which regulate thermoregulation in postmenopausal women. Their thermoregulatory activity may be involved, at least in part, in the maintenance of body core temperature in untreated postmenopausal women. In this study the chronic treatment with veralipride increased the endogenous opioid activity on body temperature. In fact,after treatment the hypothermic effect of naloxone was enhanced, suggesting that more endogenous opioid peptides are available in these subjects and may be blocked by naloxone. The enhanced activity of the endogenous opioid system induced by veralipride did not induce hyperthermia in basal conditions. Conversely the administration of both opioids and opiates to animals was shown to be able to increase body temperature (21-27). Different species and different experimental protocols could justify this discrepancy. In addition, interactions with other neurotransmitters known to be involved in the complex mechanisms of thermoregulation (30) can account for the lack of any increase of body basal temperature in postmenopausal women. The enhanced endogenous opioid activity induced by veralipride can account for a greater thermoregulatory stability, as reported in animals (21,251 and therefore for the clinical efficacy of veralipride on postmenopausal hot flushes (2,10,11). Therefore present study suggests that drugs able to improve climacteric vasomotor symptoms can stimulate and probably act through the endogenous opioid system (1,2). The specific site of action of endogenous opioid peptides and their interactions with other neurotransmitters involved in thermoregulation need further elucidations.
Acknowledgments This work was supported by the Consiglio Nazionale delle Ricerthe (C.N.R.) Rome, Italy, grants 86.00531.04 and 86.01787.56. We thank Mr. Gino Narducci, Mr. Silvano Orcesi and Mr. Emilio Madrigali for their technical assistance. Mrs. Gabriella Campani is acknowledged for her excellent secretarial assistance.
552
Veralipride-OpioidsInteractionsin Women
Vol. 42, No. 5, 1988
References ___1 . R.F. CASPER, S.S.C. YEN, Clin. Endocrinol. 22 293-312 (1985). 2 . L. ZICHELLA, P. FALASCHI, P. FIORETTI, G.B.
Vol. 42, No. 5, 1988
Veralipride-OpioidsInteractionsin Women
553
(1977). Sot. Exp. Biol. Med. -.156 523-526 (1979). 1165-1171 28. J. STEWART, R. EIKELBOOM, Life Sciences 25 29. J.W. SIMPKINS, M.J. KATOVICH, 1,.-C. SONGTLife Sciences -32 1957-1966 (1983). 40 2735-2740 (1981). 30. C.M. BLATTEIS, Federation Proc. -