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Proc. Nadl. Acad. Sci. USA Vol. 88, pp. 8544-8547, October 1991 Medical Sciences Inhibition of acute inflammation in the periphery by central action of salicylates (central nervous system modulation of nlm ti n/indomethadn/dexamethasone) ANNA CATANIA*, JOHN ARNOLD, ANTHONY MACALUSO, MELANIE E. HILTZ, AND J. M. LIPTONt Departments of Physiology and Anesthesiology, University of Texas Southwestern Medical Center at Dalias, Dallas, TX 75235-9040 Communicated by S. M. McCann, July 10, 1991 (receivedfor review January 31, 1991) ABSTRACT Understanding of the antl tory ac- The antipyretic action of these common drugs is believed tions of nonsteroidal drugs is incomplete, but these actions are to differ from their antiinflammatory action in that it must believed to occur in the periphery, without any contribution occur within the brain (8). However, because (i) a-MSH and from the central nervous system. Recent research on the antipyretic/antiinflammatory drugs have similar effects; (ii) antipyretic antUnflammatory neuropeptide a-melanocyte- the drugs, whether given centrally or peripherally, act within stimulating hormone indicates that it can act centrally to inhibit the brain to inhibit fever; and (iii) as stated above, central peripheral inflatlon; this raises the possibility that other injection of a-MSH inhibits acute inflammation in the pe- agents, such as nonsteroidal antilnflammatory drugs, may have riphery, it may be. that NSAIDs likewise act centrally to similar activity. In the present research both lysine acetylsa- influence inflammation. To test this idea, NSAIDs were licylate and sodium salicylate inhibited edema, induced in the administered i.c.v. to mice with acute cutaneous inflamma- mouse ear by topical application of picryl chloride, when tion induced by local application of picryl chloride. injected into the lateral cerebral ventricle. This inhibitory activity on a measure of acute flammation was not due to AND escape of the drugs into the periphery, because systemic MATERIALS METHODS iqjection of doses that were effective centrally did not affect Female BALB/c mice (Simonsen Laboratories, Gilroy, CA), inflammation. In contrast, central admintion of a dose of 7 weeks old, were housed at 23-250C (range) in groups not indomethain-that was antfmmatory when given intraperi- exceeding five per cage (28 cm long x 18 cm wide x 13 cm toneally did not inhibit peripheral ifmmation. Thus indo- high). They were acclimatized under standard conditions for methacin apparently lacks the central antiinflammatory action at least 1 week with food and water freely available. Several of the salicylates. This observation, plus our inability to shipments of mice were required for these experiments, and demonstrate either an antlinflammator effect of intracere- the base-line inflammatory response to picryl chloride is broventricular dexamethasone, a prostaglandin inhibitor, or a known to differ slightly among animals from different ship- pro-inlammatory influence of prostaglandin E%, suggts that ments. For this reason, tests of specific agents were per- prglandins are not important to central modulation of formed as separate experiments in which experimental and inflammation. The results indicate that, in addition to having control animals in each study were drawn from the same -central-Influences on feverand pain, salicylates can act within shipment. the brain to inhibit acute inflammation, in the periphery. Each animal was anesthetized with 10%o pentobarbital sodium solution (50 mg/kg; Nembutal; Abbott). Base-line Hypotheses about the mechanisms of action of antiinflam- thickness of both ears was measured with a spring-loaded matory drugs have focused on peripheral actions such as micrometer (Swiss Precision Instruments, Los Angeles). To inhibition of hydrolytic enzymes, metabolism of arachidonic induce ear edema, a classic sign of acute inflammation, both acid, and migration ofpolymorphonuclear leukocytes, mono- sides of each ear were coated with 10- jul (44) /l total per cytes, and lymphocytes into injured tissue (1). More recently, mouse)- of 0.5% picryl chloride in acetone (9). Immediately local cytokines such as tumor necrosis factor-and interleukin thereafter, an NSAID, dexamethasone, or prostaglandin E2 1 have been linked to- inflammation (2). Although the central (PGE2), dissolved in nonpyrogenic saline (20 IL), or saline nervous system (CNS} was identified as a possible target for alone (20 /ul), was injected directly into a lateral cerebral the action of nonsteroidal antiinflammatory drugs (NSAIDs) ventricle of each anesthetized mouse. The general technique in pioneering studies (3), modem reviews of antiinflamma- has been described previously (10). The animals were anes- tory agents do not mention any influence of the CNS (e.g., thetized again 3 and 6 hr later, and ear swelling was deter- refs. 4 and 5). However, recent observations indicate that mined by subtracting the base-line thickness from the mea- peripheral acute inflammation characterized by edema can be surements obtained foreach ear at 3 and 6 hr. The differences inhibited by a central action of the neuropeptide a-melano- for the two ears were averaged for the final analysis. The cyte-stimulating hormone (a-MSH; melanotropin); local ap- NSAIDs lysine acetylsalicylate (Maggioni-Winthrop, Milan), plication of picryl chloride to the mouse ear evoked edema sodium salicylate (Fisher Scientific), and indomethacin were that was inhibited in a dose-dependent fashion by intracere- tested. The salicylates were selected both because of their broventricular (i.c.v.) administration of this peptide (6). The potent antiinflammatory activity and because they are solu- effect on- edema could not be traced to an a-MSH-induced ble in water and can therefore be readily injected into the increase in circulating corticosterone, a glucocorticoid that brain. A water-soluble form of indomethacin, sodium indo- has marked antiinflammatory activity. a-MSH, like common antipyretic drugs, also reduces fever when given centrally or Abbreviations: CNS, central nervous system; NSAIDs, nonsteroidal peripherally (7). antiinflammatory drugs; a-MSH, a-melanocyte-stimulating hormone (a-melanotropin); i.c.v., intracerebroventricular(ly); PGE2, pros- taglandin E2. The publication costs ofthis article were defrayed in part by page charge *Present address: First Medical Clinic, University of Milan, 20122 payment. This article must therefore be hereby marked "advertisement" Milan, Italy. in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 8544 Downloaded by guest on September 23, 2021 Medical Sciences: Catania et al. Proc. Natl. Acad. Sci. USA 88 (1991) 8545 I.C.V. ' P - 10C0 u Car i:. J) _ C) * i 5.0 l} * ** .a_ 25 On*a) or- :I. 0 0 _- ; 25 50 1 So c 25 50 100 vysir~e aceiy'sa{cvya'e C LOs!10': FIG. 1. Inhibition of peripheral edema by centrally administered FIG. 3. Sodium salicylate (100 Mg) inhibited inflammation when lysine acetylsalicylate._ Scores in this and following figures are mean given i.c.v. but not when given i.p. + SEM changes in ear thickness. Number of animals (n) is given above each bar. The probability refers to comparisons with control To learn whether the central antiinflammatory effect is values at the same time after administration ofthe agent: *, P < 0.05; limited to the specific molecular conformation of lysine **, P < 0.01; ***, P < 0.0001. acetylsalicylate, 100 ug of sodium salicylate was adminis- tered both i.c.v. and i.p. (Fig. 3). Given centrally, this agent methacin trihydrate (courtesy of C. M. Stemmler, Merck likewise inhibited acute inflammation of the ear (F = 38.9, P Sharp & Dohme), was tested for the same reasons and < 0.0001). The inhibition of edema was approximately 30%o because of its marked inhibitory effect on prostaglandin at 3 hr and 44% at 6 hr. As with lysine acetylsalicylate, i.p. synthesis. Dexamethasone and PGE2 were obtained from administration of the same dose had no influence (F = 3.19, Sigma. P = 0.89). Analysis of variance techniques (Dynastat, Philadelphia) To test further the generality of the central action of were used to test for significant overall differences in sepa- NSAIDs on acute inflammation, indomethacin was adminis- rate analyses for each agent. The Student-Newman-Keuls teredcentrally. A dose of 100Mug had no effect on edema(Fig. test was used to compare specific differences in the mean 4). One milligram was not only ineffective, it killed two offive effects of control and drug treatments. mice in initial tests. When 100 ,ug of indomethacin was given i.p., itdid inhibit the edema (F = 18.1, P < 0.0001). Inhibition was 51% at 3 hr and 42% at 6 hr. RESULTS Dexamethasone, a potent synthetic glucocorticoid be- Lysine acetylsalicylate administered i.c.v. inhibited acute lieved to inhibit inflammation locally, in part by inhibition of peripheral inflammation (Fig. 1, F = 10.35, P < 0.0001). arachidonic acid release, was administered in a dose judged was inhibited in a dose-related fashion at to beover 6-fold more effective than a prednisolone dose that Edema 3 hr, with a had previously been shown, when given i.p., to inhibit mean maximum of41% inhibition after the 100l-1g dose; only inflammation in the mouse ear (9). Dexamethasone had no this dose remained effective at 6 hr (53% inhibition). The inhibitory action on peripheral edema when injected i.c.v. antiinflammatory influence of central lysine acetylsalicylate (Fig. 5). Rather, there was a small but significant increase in was not secondary to- escape of the drug into the periphery, ear swelling at 3 hr. because neither the largest effective central dose (100 jg) nor To test the idea raised by the indomethacin and dexameth- a dose 10-fold greater had any effect on inflammation when asone results that central prostaglandins are not important to given i.p. (Fig. 2). On the other hand, a systemic dose of 10 modulation of peripheral inflammation, PGE2 or saline was mg did inhibit inflammation, perhaps consistent with suffi- injected i.c.v.

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