Can Haloperidol Disguise Fever?

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1 Physil. Res. 43: , 1994 Can Halperidl Disguise Fever? S. VYBÍRAL, R. VESELÁ Department f Physilgy and Develpmental Bilgy, Faculty f Science, Charles University, Prague, Czech Republic Received May 24, 1994 Accepted Octber 3, 1994 Summary Halperidl when applied intraperitneally t cld-expsed febrile rabbits induces a strng hypthermic effect. This effect is due t the dwnward shift f the threshld central temperature fr inductin f cld thermgenesis and vasmtin. The shift ccurs during the early phase f the fever and is less prminent during the late phase f the fever. The hypthermic effect f high dses f halperidl can eliminate the increase f bdy temperature in febrile individuals. Key wrds Fever - Halperidl - Thermregulatry threshlds Intrductin Halperidl, a dpamine antagnist, is being extensively used as a neurleptic substance. Interacting with D2 receptrs it has als a central depressive effect n thermregulatin in warm- as well as cld-expsed subjects (fr review see Clark and Liptn 1991). In nrmthermic rabbits intraperitneal injectins f halperidl induce a striking shift f the threshld temperature fr inductin f thermregulatry utputs t lwer bdy temperature, withut influencing their intensity and hypthalamic thermsensitivity. Intrahypthalamic injectins f halperidl are withut effect r induce mild hyperthermia, due t depressin f panting and peripheral vasmtr tne (Vybíral and Janský 1989). Fig-1 Experimental set-up. intestinal cling device

2 360 Vybíral, Veselá Vl. 43 PVMT 35 u <U 30 Q. E c L* 25 *#> 5.0 _ CT U E 36 hypthalamic temperature ( C) Fig. 2 Relatinship between the bdy cre temperature and intensity f individual thermregulatry effectrs (CT - cld thermgenesis, PVMT - peripheral vasmtr tne) during intestinal cling in cntrl febrile rabbits (pen circles) and in febrile rabbits given halperidl (2.5 mg.kg-1 i.p.) (clsed circles) in the early phase f endtxin fever (LPS 5^g.kg-1 i.v.). Means ± S.E.M frm 6 experiments. (Cntrl data fr endtxin and fr endtxin + halperidl are nt given.)

3 1994 Can Halperidl Disguise Fever? 361 hypthalamic temperature ( C) Fig. 3 Relatinship between the bdy cre temperature and intensity f individual thermregulatry effectrs (CT - cld thermgenesis, PVMT - peripheral vasmtr tne) during intestinal cling in cntrl febrile rabbits (pen circles) and in febrile rabbits given halperidl (2.5 mg.kg-1 i.p.) (clsed circles) in the late phase f endtxin fever (LPS 5 /ig.kg-1 i.v.). Fr ther details see Fig. 2.

4 362 Vybíral, Veseiá Vl. 43 Tw phases f the thermregiil; te r respnse can be distinguished in the curse f ťsver (Vybíral et al. 1987, Iriki et al. 1984, Hashimt et al. 1985). During the early phase f the fever, ccurring within the first 100 min, the increase in bdy temperature is due t the shift f threshld bdy temperature fr inducing f cld thermgenesis, panting and release f the peripheral vasmtr tne t higher bdy temperatures. The late phase f the fever is characterized by a dwnward shift f the threshld bdy temperature fr shivering, while that fr vasmtin remains elevated, s that a dissciatin f threshlds fr cld and warm defence mechanisms ccurs. The capacity f cld thermgenesis during the endtxin fever is reduced. The effect f intraperitneal injectins f halperidl n thermregulatin in the early and/r late phase f fever has nt yet been studied and the mde f halperidl actin n thermregulatry centres has nt been elucidated. L (O. -> \ ~ r ~ \ A- / \ f / \ \ Q. / a \ / \ 0 / \ / * \ A \ ' / t : Methds Thermregulatry functins f rabbits were analysed by means f the methd f intestinal cling (Inmt et al. 1982) (Fig. 1). This methd enables the manipulatin f central bdy temperature while leaving the peripheral bdy temperature relatively unaffected. The values f cld thermgenesis (CT - measured as xygen cnsumptin) and peripheral vasmtr tne (PVMT - ear skin temperature) were mnitred at 3 min intervals, first in nrmal rabbits (receiving an injectin f pyrgen-free saline) during intestinal cling till cld thermgenesis is fully activated. After rewarming f animals, the tested substances (lipplysaccharide - LPS and halperidl) were injected and intestinal cling was repeated. Values f xygen cnsumptin and skin temperature were then expressed as functins f central bdy temperature measured in the hypthalamus. On the basis f these data it was pssible t determine the capacity and the threshld temperature fr inductin f individual thermregulatry effectrs (CT, PVMT) as well as the thermsensitivity f hypthalamic cntrl centers. Further methdical details are given in the paper f Vybíral et al. (1986). Halperidl was administered intraperitneally in a dse 2.5 mg.kg-1 t rabbits made febrile by the intravenus injectin f lipplysaccharide (S. typhsa 5 pg. kg-1). Halperidl was injected immediately after injectin f LPS r 120 min later, i.e. in the early r in the late phase f the fever. In bth cases intestinal cling was started 18 min after administratin f halperidl. tem perature changes ( C) Fig. 4 Scheme f activatin f individual thermregulatry effectrs (CT, PVMT) due t changes in central bdy temperature in cntrl rabbits (dtted line), after halperidl (2.5 mg.kg-1 i.p.) (dashed line) (panel A) as well as in cntrl febrile rabbits (S. typhsa 5/^g.kg-1 i.v.) (full line) and in febrile rabbits given halperidl (brken line) in the early (panel B) r the late (panel C) phases f the fever. Results and Discussin Intraperitneal injectins f halperidl in the early phase f the fever induce a hypthermic effect due t a shift f the threshlds fr cld thermgenesis and peripheral vasmtr tne t lwer bdy temperatures (Fig. 2 and 4B). The shift f the threshld bdy temperature fr shivering is mre prminent than that fr vasmtin, the cnsequence being an enlargement f the interthreshld zne when thermregulatin is nt activated. The earlier results

5 1994 Can Halperidl Disguise Fever? 363 bserved in nrmthermic rabbits given halperidl (Fig. 4A) (Vybíral and Janský 1989) indicate that the hypthermic effect f this substance in the early phase f the fever fund in this study is cnnected with the febrile prcess. The effect f the same dse f the i.p. applied halperidl in the late phase f the fever des nt influence the already lwered threshld fr cld thermgenesis (Fig. 3 and 4C). The threshld fr inductin f the peripheral vasmtr tne is slightly lwered, hwever, s that the interthreshld zne becmes narrwer. Thus the halperidl effect in the late phase f the fever is similar t that f ACTH, AVP and ther natural antipyretic substances (Vybíral et al. 1988, Ehymayed and Janský 1992). Thugh it is generally accepted that the peripherally injected halperidl penetrates int the brain, ur previus experiments (Vybíral and Janský 1989) indicate that intrahypthalamically injected halperidl has rather a hyperthermic effect. The reasn fr this discrepancy remains unclear. Our data indicate that heavy dses f halperidl when applied t febrile subjects can bscure fever. References CLARK W.G., LIPTON J.M.: Drug-related heat strke. In: Thermregulatin: Pathlgy, Pharmaclgy and Therapy. E. SCHÖNBAUM, P. LOMAX (eds), Pergamn Press, New Yrk 1991, pp EHYMAYED H.M., JANSKÝ L.: A discrete mde f the antipyretic actin f AVP, a-msh and ACTH. Physil. Res. 41: 57-61, HASHIMOTO M,, NAGAI M., IRIKI M.: Cmparisn f the actin f prstaglandin with endtxin n thermregulatry respnse threshlds. Pflügers Arch. 405:1-4,1985. INOMOTO T., MERCER J.B., SIMON E: Oppsing effect f hypthalamic cling n threshld and sensitivity f metablic respnse t bdy cling in rabbits. J. Physil. Lnd.. 322: ,1982. IRIKI M., HASHIMOTO M., RIEDEL W.: Threshld dissciatins f thermregulatry effectr respnses in febrile rabbits in warm envirnment. In: Thermal Physilgy. J.R.S. HALES (ed.), Raven Press, New Yrk 1984, pp VYBÍRAL S., ČERNÝ L., JANSKÝ L.: Mde f ACTH antipyretic actin. Brain Res. Bull. 21: , VYBÍRAL S., JANSKÝ L.: The rle f dpaminergic pathways in the thermregulatin in the rabbit. Neurpharmaclgy 28:15-20,1989. VYBÍRAL S., NACHÁZEL J., JANSKÝ L.: Hyperthermic effect f neurtensin in the rabbit. Pflügers Arch. 406: ,1986. VYBÍRAL S., SZEKELY M., JANSKÝ L., ČERNÝ L.: Thermregulatin f the rabbit during the late phase f endtxin fever. Pflügers Arch. 470: , R eprint requests Dr. S. Vybíral, Department f Physilgy and Develpmental Bilgy, Faculty f Science, Charles University, CZ Prague 2, Viničná 7, Czech Republic.

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