Mini-Review

Interleukin-1 and Nociception in the RatMauro Bianchi,1* Bassam Dib,2 and Alberto E. Panerai11Department of Pharmacology, University of Milano, Milano, Italy2Laboratoire de Physiologie de l’Environnement, Universite´ Claude Bernard Lyon 1, Lyon, France

It has recently become accepted that several cytokinesmay affect peripheral and central nervous systemfunctions. Consistently with these findings, accumulat-ing evidence points toward an important role forinterleukin-1 in the modulation of nociceptive informa-tion. Here we review the observations collected afterthe administration of this cytokine by intracerebroven-tricular, intrathecal or peripheral route in rats. Takentogether, these data suggest that IL-1 can differentlyaffect pain responsivity depending on the dose and thesite of action, and clearly demonstrate that thisimmune factor is deeply involved in the modulation ofneuronal functions. J. Neurosci. Res. 53:645–650,1998. r 1998 Wiley-Liss, Inc.

Key words: brain; hyperalgesia; interleukin-1; noci-ceptive thresholds; spinal cord

INTRODUCTIONIn the last years it has been demonstrated that a

bidirectional circuit exists between the immune systemand the nervous system. Consistently with this interac-tion, it has been reported that several mediators releasedfrom immune cells exert neuromodulatory and neuroendo-crine effects (Black, 1994; Besedowsky and Del Rey,1996).

Interleukin-1 (IL-1) is one of the earliest membersof this group of protein mediators now known as thecytokines to have been identified, and it exhibits diverseactivities on several biological functions (Aggarwal andPocsik, 1992). IL-1 is a polypeptide produced by a largevariety of cells (including macrophages, fibroblast, kera-tinocytes, synoviocytes, mast cells, glial cells, and neu-rons), as a result of infection, toxic injury, trauma orantigenic challenge (Mizutani et al., 1991; Dinarello,1992).

IL-1 is present in two molecular forms, IL-1a andIL-1b; the two forms of IL-1 are the products of differentgenes, but both are sinthesyzed as 31 kDa precursors thatare processed to produce 17 kDa C-terminal fragments;moreover, they are structurally related at the three-dimensional level (Dinarello, 1991). The overall homol-

ogy between the two forms is approximately 25%, whilethe homology across any two animal species varies from60–80% (Scho¨bitz et al., 1994).

IL-1 mediates its action on target cells via high-affinity receptors on the plasma membrane. Two IL-1receptors, termed IL-1RI and IL-1RII, have been identi-fied (Cunningham and De Souza, 1993). Despite thedifferences in their amino acid sequences, IL-1a andIL-1b bind to both IL-1 receptor subtypes, and sharebiologic activities (Plata-Salama`n, 1991; Dinarello andWolff, 1993).

It has been demonstrated that IL-1 (and othercytokines such as tumor necrosis factor and IL-6) duringinflammation, injury, and infection produces severalneural changes that have been called ‘‘illness responses’’(Watkins et al., 1995). Moreover, IL-1 can be producedand act locally within the brain to influence neuronal andglial functions (Breder et al., 1988; Van Dam et al., 1992;Yabuuchi et al., 1994). It has been recently suggested thatbrain IL-1 might mediate the effects of some centrally-injected drugs; indeed, the enhancement of nociceptivethresholds to a mechanical stimulation observed after theintracerebroventricular administration of isoproterenol (ab-adrenoceptor agonist) in the rat is associated with asignificant increase of IL-1b expression in the brain(Yabuuchi et al., 1997). A number of mechanisms ofaction have been proposed to explain the diverse effectsof IL-1 in the central nervous system, probably involvingcomplex interactions with neurotransmitters and neuropep-tides (Palazzolo and Quadri, 1990; Rothwell, 1991;Watkins et al., 1995).

Recently, it has been discovered a naturally occur-ring IL-1 specific receptor antagonist (IL-1ra), whichbinds to IL-1 surface receptors but does not possessagonist activity and acts as a competitive inhibitor of IL-1(Dinarello, 1992). IL-1ra shows 19% homology to IL-1a

and 26% to IL-1b (Eisenberg et al., 1990). Lackingbiological activity, this antagonist can be given in doses

*Correspondence to: Mauro Bianchi, M.D., Department of Pharmacol-ogy, Via Vanvitelli, 32, 20129 Milano, Italy. E-mail: m.bianchi@airon.it

Received 29 April 1998; Revised 4 June 1998; Accepted 8 June 1998

Journal of Neuroscience Research 53:645–650 (1998)

r 1998 Wiley-Liss, Inc.

sufficient to occupy IL-1 receptors and therefore preventthe binding of IL-1. Considerable information on thephysiological and pathological role of IL-1 has accumu-lated by using this peptide antagonist. The role exerted byIL-1 in the modulation of pain mechanisms has been thefocus of intense study over the past decade. This shortreview will consider the data concerning the effects ofIL-1 on nociception in the rat.

EFFECTS OF CENTRALLYADMINISTERED IL-1

Intracerebroventricular (i.c.v.) Injection

Central administration of IL-1 in rats produces avariety of effects, such as fever, behavioural modifica-tions, alterations in brain monoamines, and modulation ofimmune function (Rothwell and Luheshi, 1994; Sacer-dote et al., 1994). With reference to nociception, it hasbeen demonstrated that the i.c.v. administration of IL-1 inrats modulates thermal and mechanical nociception. Inconformity with the initial observations performed inmice by Nakamura and colleagues on chemical nocicep-tion (Nakamura et al., 1988), we previously reported thatthe i.c.v. administration of large doses of human recombi-nant IL-1a (15–85 ng/kg) produced short lasting analge-sia as assessed by the hot-plate test (Bianchi et al., 1991).Such increase in nociceptive thresholds was not affectedby the opiate receptor antagonist naloxone, or antiseraagainst the endogenous opioidsb-endorphin, met-enkephalin and dynorphin. Moreover, the analgesic ac-tion of IL-1 was not mediated by prostaglandins, since itwas not prevented by the administration of the cyclooxy-genase inhibitor indomethacin. It is important to notethat, at the same doses, IL-1 did not affect spontaneouslocomotor activity as measured by the Animex test(Bianchi et al., 1992).

Subsequently, we demonstrated that the i.c.v. pre-treatment with 6-hydroxydopamine (i.e. the depletion ofbrain catecholamines) or i.p. prazosin (a blocker ofa1

adrenoreceptors) prevented the antinociceptive effect ofIL-1a. Moreover, the i.c.v. administration of the corticotro-pin-releasing hormone antagonista-helical CRH [9-41]completely blocked the increase of nociceptive thresholdsinduced by IL-1a (Bianchi and Panerai, 1995). Thus, bothCRH and noradrenergic system seem to be involved inthe antinociceptive effects of i.c.v. administered IL-1. It isinteresting to note that an involvement of CRH in theantinociceptive action of IL-1 has been reported also inmice (Kita et al., 1993).

Opposite results have been obtained using lowerdoses of IL-1. In this perspective, we must considerseveral papers by Oka and colleagues. These authorsreported that the i.c.v. administration of human recombi-

nant IL-1b at nonpyrogenic doses (10 pg/kg to 1 ng/kg),was able to induce hyperalgesia, with the maximalresponse at a dose of 100 pg/kg. Interestingly, thehyperalgesic action of IL-1 was inhibited by pretreatmentwith IL-1ra or a-melanocyte-stimulating hormone (a-MSH), but not by the pretreatment with the corticotropin-releasing hormone antagonista-helical CRH [9-41] (Okaet al., 1993). Moreover, the i.c.v. injection of low doses ofIL-1b enhanced the response of wide dynamic range(WDR) neurons in the trigeminal nucleus caudalis tonoxious pinch. This effect of IL-1 was completelyabolished by pretreatment with either IL-1ra,a-MSH orsodium salicylate (Oka et al., 1994).

Taken together, these findings indicate that IL-1exerts biphasic effects on thermal nociceptive thresholdsdepending upon the dose: lower doses cause hyperalge-sia, whereas higher doses are analgesic.

The biphasic effects of i.c.v. IL-1 were also de-scribed when the effects of the cytokine on mechanicalnociception were evaluated. Indeed, it has been demon-strated that the injection of IL-1b at doses of 40 and 400pg/kg caused hyperalgesia, whereas higher doses (4 and40 ng/kg) induced an analgesic effect that was evidentbetween 120 and 180 min after the administration of IL-1(Yabuuchi et al., 1996). The coadministration of IL-1raantagonized both the hyperalgesic and the analgesicaction of IL-1. Similar observations were performed afterthe injection of corticotropin-releasing hormone antago-nista-helical CRH [9-41] 15 min prior to IL-1 administra-tion. By contrast, pretreatment with sodium salicylateinhibited the hyperalgesic effect of the cytokine, but notits analgesic effect (Yabuuchi et al., 1996). Therefore,different mechanisms seem to be involved in the analge-sic and hyperalgesic effects of i.c.v. injected IL-1 (Table Iand II).

Finally, it is important to note that the effectsobserved following i.c.v. administration of IL-1 cannot beaccounted for by diffusion to the periphery, since theeffective i.c.v. doses (or larger doses) were ineffectivewhen given systemically (Bianchi et al., 1992; Watkins etal., 1994).

TABLE I. Mechanisms Involved in the Enhancementof Nociceptive Thresholds Induced by the i.c.v. Administrationof IL-1 in Rats*

Mechanism Yes/Not Reference

IL-1 receptors Yes Yabuuchi et al., 1996CRH Yes Bianchi and Panerai, 1995PGs Not Bianchi et al., 1992Opioid receptors Not Bianchi et al., 1991, 1992Adrenoreceptors Yes Bianchi and Panerai, 1995

*PGs5 Prostaglandins; CRH5 Corticotropin-Releasing Hormone.

646 Bianchi et al.

Injection Into Specific Brain RegionsIn order to elucidate the precise sites in the brain

where IL-1 exerts its action on nociception, the effects ofmicroinjections of IL-1b into the hypothalamus andneighbouring brain areas on nociceptive behavior werestudied in rats using a hot-plate test (Oka et al., 1995).The injection of IL-1 into the medial part of the preopticarea (MPO) reduced the nociceptive thresholds. Similareffects were observed after the injection into the lateralpart of the preoptic area, the median preoptic nucleus andthe diagonal band of Broca. The dose of IL-1 whichinduced the maximal hyperalgesic effect by intra-MPOinjection was fives times lower than that necessary toproduce an equivalent hyperalgesia by i.c.v. injection(Oka et al., 1993). The hyperalgesia induced by IL-1 wasblocked by the simultaneous injection of IL-1ra, anda-MSH.

On the contrary, the injection of the cytokine intothe ventromedial hypothalamus (VMH) produced a pro-longation of the paw-withdrawal latency. This reactionwas blocked by IL-1ra, as well as by sodium salicylate.The VMH stimulation-induced analgesia is known to bemediated by the activation of the inhibitory systems ofnociception in the lower brainstem (Takeshige et al.,1992). Therefore, the authors suggest that IL-1 inhibitsthe POA-mediated inhibitory pathway, and excites theVMH-mediated inhibitory pathway (Oka et al., 1995).

Intrathecal InjectionThe effects of the spinal administration of IL-1 on

nociception have been evaluated using hot-plate, tail-flickand paw pressure test. We have recently observed that i.t.IL-1b (500 pg to 5.0 ng i.t.) induced a significanthyperalgesic effect in the hot-plate test, but not in thetail-flick test (Dib and Bianchi, unpublished observa-tions). These data are consistent with the observation thatthe administration of a high dose of IL-1b (50 ng) byintrathecal route did not produce any effect in nociceptivethresholds as assessed by tail-flick test (Watkins et al.,1994). Nociceptive thresholds to mechanical stimuli wereenhanced by the administration of IL-1b (10–1000 ng) byintrathecal route (Takano et al., 1996).

Finally, it is interesting to note that the hyperalgesiainduced by s.c. formalin is significantly enhanced by thespinal administration of IL-1 (Takano et al., 1996), andreduced by the spinal administration of IL-1ra (Watkins etal., 1995).

Taken together, these observations suggest a rolefor spinal IL-1 in mechanisms underlying hyperalgesicstates (Meller et al., 1994, Watkins et al., 1997).

EFFECTS OF PERIPHERALLYADMINISTERED IL-1Intra-Peritoneal (i.p.) Injection

Although different mechanisms have been proposedto explain how immune signals reach the brain (Banks etal., 1989; Rothwell and Luheshi, 1994), there is clearevidence that i.p. injection of IL-1 does alter neuralactivity in mice and rats (Bianchi et al., 1995; Dunn et al.,1991). The i.p. injection of IL-1b at a dose of 10 µg/kg hasbeen shown to produce hyperalgesia as assessed bytail-flick test (Watkins et al., 1994). Similar results wereobtained when nociceptive thresholds were evaluatedusing a hot-plate test. Interestingly, the hyperalgesiainduced by i.p. IL-1 was inhibited by the i.c.v. injection ofboth diclofenac anda-MSH, thus suggesting that centralmechanisms are involved in the development of hyperal-gesia induced by the i.p. administration of IL-1, inaddition to peripheral ones (Oka et al., 1996). Moreover,there is evidence that peripherally-administered IL-1affects brain functions and nociceptive behavior, at leastin part, by activating vagal afferents (Watkins et al.,1995).

Intra-Plantar (i. pl.) InjectionInflammation is often associated with pain and

hyperalgesia, and it is clear that some of the agentsproduced during inflammation can activate primary affer-ent neurones, either directly or indirectly. A variety ofcytokines including IL-1 appears to be involved innociceptor sensitization (Levine et al., 1993; Jeanjean etal., 1994). Many data about the involvement of IL-1 innociceptive processes derive from research in which IL-1was administered in peripheral tissues, and inflammatoryparameters have been evaluated (Hrubey et al., 1991;Ferreira et al., 1993a). Several observations suggest a rolefor IL-1 in the peripheral modulation of nociception. Inparticular, it has been demonstrated that, when adminis-tered subcutaneously in the rat paw, IL-1b is able toproduce a dose-dependent increase in the sensitivity tonoxious stimulation (Ferreira et al., 1988; Follenfant etal., 1989; Cunha et al., 1991).

Electrophysiological studies have shown that small-diameter cutaneous nerves are activated by the local (s.c.)

TABLE II. Mechanisms Involved in the Reduction of NociceptiveThresholds Induced by the i.c.v. Administration of IL-1 in Rats*

Mechanism Yes/Not Reference

IL-1 receptors Yes Yabuuchi et al., 1996CRH Not Oka et al., 1993PGs Yes Oka et al., 1994a-MSH Yes Oka et al., 1993

*PGs 5 Prostaglandins; CRH5 Corticotropin-Releasing Hormone;a-MSH 5 a-Melanocyte-Stimulating Hormone.

Interleukin-1 and Nociception 647

injection of IL-1b in rats (Fukuoka et al., 1994). More-over, by using antisera neutralizing endogenous IL-1b ithas been shown that IL-1 is involved in the inflammatoryhyperalgesia produced by carrageenin (Cunha et al.,1992), and bradykinin (Ferreira et al., 1993b). Morerecently, new considerable information on the physiologi-cal and pathological role of IL-1 has accumulated byblocking IL-1 receptors with the IL-1 receptor antagonist.Using IL-1ra it has been demonstrated that endogenousIL-1 is involved in the inflammatory hyperalgesia pro-duced by the intraplantar injection of complete Freund’sadjuvant, or endotoxin in rats (Safieh-Garabedian et al.,1995; 1997). Recently, we evaluated the effects of theintraplantar administration of IL-1ra on the nociceptivethresholds to a mechanical stimulus in normal andinflamed rat paw, and on pain-related behavior in the ratpaw formalin test. We observed that formalin-inducednociceptive behavior was significantly reduced by thepre-treatment with IL-1ra (Giuliani et al., unpublisheddata).

CONCLUSIONSAlthough some report failed to demonstrate any

effect on nociception after i.c.v. injection of IL-1 (Adamset al., 1993), the results obtained in the past decadeclearly demonstrate that centrally injected IL-1 hasmodulatory effects on nociceptive transmission. How-ever, the direction of these effects (analgesia or hyperalge-sia), as well as the brain regions involved in the analgesicor hyperalgesic effects of IL-1, appear to be controversial.As cited above, it seems reasonable to suggest that i.c.v.IL-1 exerts biphasic effects on nociceptive thresholdsdepending upon the dose: lower doses cause hyperalge-sia, whereas higher doses are analgesic.

Since the analgesic effect of i.c.v. IL-1 was notaffected by the pretreatment with i.c.v. sodium salicylateor i.p. indomethacin (Yabuuchi et al., 1996; Bianchi et al.,1992), a cyclooxygenase-dependent pathway does notseem to be involved in this action of the cytokine. On theother hand, it has been demonstrated that the analgesiceffects of i.c.v. IL-1 was inhibited by the prior administra-tion of a CRH receptor antagonist (Bianchi and Panerai,1995; Yabuuchi et al., 1996), indicating that the antinoci-ceptive action of IL-1 is mediated by endogenous CRH.On the contrary, the hyperalgesic effect of i.c.v. IL-1 wasblocked by the pretreatment with sodium salicylate (Okaet al., 1994; Yabuuchi et al., 1996), but not by theadministration of the corticotropin-releasing hormoneantagonista-helical CRH [9-41] (Oka et al., 1993). BothIL-1-induced hyperalgesia and analgesia are mediated byIL-1 receptors, since these two opposite effects areblocked by the pretreatment with a specific IL-1 receptorantagonist.

When IL-1 was delivered intrathecally differentresults have been obtained (Watkins et al., 1994; Takanoet al., 1996; Dib and Bianchi, unpublished observations).However, an analysis of the data available in the literaturesuggest a role of IL-1 (probably produced by glial cells)in nociceptive processing in the rat spinal cord. Thisraises the possibility that several hyperalgesic states maybe influenced by substances classically thought as im-mune mediators (Watkins et al., 1997). Several datasuggest that, after i.p. injection, IL-1 induces hyperalge-sia via activation of vagal afferents (Watkins et al., 1994).

Although one report suggests an anti-inflammatoryeffect of the intraplantarly injected IL-1b (Drelon et al.,1994), most experiments have shown a central role forIL-1 in the pathophysiology of inflammatory pain andhyperalgesia (Schweizer et al., 1988; Fukuoka et al.,1994; Safieh-Garabedian et al., 1995). Consistently withthis hypothesis, it has been suggested that the effects ofseveral anti-inflammatory and analgesic drugs may beattributable to the inhibition of IL-1 effects in periphery(Ferreira, 1994). Although it is clear that IL-1 canfacilitate pain in periphery, it is not at all clear themechanisms of these effects, and which substances aredirectly responsible for activating peripheral nerve fibers.Further studies are necessary to elucidate this point. Itmay in fact turn out that IL-1 might cause the release ofagents that could affect other cells or stimulate peripheralnociceptors (Levine et al., 1993). For example, it has beendemonstrated that IL-1 induces E-type prostaglandin(PG) production in non-neuronal cells (Dayer et al.,1986). PG-E2 is considered as a nonpeptide agent thatdirectly sensitize primary afferent nociceptors (Levine etal., 1993), and mediates inflammatory hyperalgesia(Safieh-Garabedian et al., 1997). IL-1 can, in addition,induce nerve growth factor (NGF) production in anumber of cell types (Yoshida and Gage, 1992), and anelevation in cutaneous NGF levels after intraplantarinjection in rats (Safieh-Garabedian et al., 1995). It hasrecently become apparent that NGF plays a major role inthe development of inflammatory hyperalgesia (Lewin etal., 1994). Moreover, IL-1 has been demonstrated to beable to stimulate the synthesis and release of transforminggrowth factor-beta (TGF-b) in many peripheral cells ofhumans and rats (Villiger et al., 1993; Offner et al., 1996;Yue et al., 1994). TGF-b might, in turn, induce the releaseof pro-inflammatory cytokines such as IL-1 and IL-6from other cells (Schluns et al., 1997). Finally, it isimportant to recognize that IL-1 in skin induces therelease of substance P (SP) from peripheral nerve termi-nals (Perretti et al., 1993). SP is able to degranulate mastcells (Mousli et al., 1994), stimulates macrophages torelease TNF, IL-1, and IL-6 (Lotz et al., 1988), andinduce inflammatory responses in the skin (Walsh et al.,1995). Therefore, several cells and mediators may be

648 Bianchi et al.

involved in the effects observed after the peripheralinjection of IL-1.

In conclusion, what does this all mean? Untilrecently, immune cells and glia have been ignored aspotential elements in neuronal signaling, and pain modu-lation. However, the data briefly reviewed here supportthe notion that they are key factors in the modulation ofnociceptive inputs (Maier et al., 1994). We hope thatthese new findings may offer new perspectives not onlyfrom the speculative, but also from the therapeutic pointof view.

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