![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
INFLAMMATION AND IMMUNOPHARMACOLOGY
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil (W.A.V., R.O.M., I.R.S.S., T.M.C., C.A.P., S.H.F., F.Q.C.); and National Institute of Biological Standards and Control, South Mimms, Hertfordshire, United Kingdom (S.P.)
Received May 11, 2005; accepted July 13, 2005.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
-methylleucyl-D-1-methoxycarboyl-D-norleucine (BQ788) (ETB receptor antagonist; 3-30 nmol paw-1) did inhibit IL-12 hyperalgesia. Furthermore, neither pretreatment with effective doses of antiserum against rat-TNF-
(50 µl paw-1) nor against IL-18 (10 µg paw-1) inhibited the IL-12-induced hyperalgesia. Likewise, antiserum against IL-12 (10 ng paw-1) did not alter IL-18-induced hyperalgesia. In conclusion, we demonstrated for the first time that IL-12 is a prohyperalgesic cytokine that induces mechanical hyperalgesia mediated by endothelin action on the ETB receptor. Therefore, endothelin receptor antagonism could be beneficial in controlling IL-12 therapy-induced pain or hyperalgesia.
). It is produced by a variety of cells including monocytes, neutrophils, B lymphocytes, macrophages, and dendritic cells, stimulated by pathogenic organisms such as bacteria, parasites, viruses, and fungi. IL-12 regulates both innate and adaptive immunity, being a key cytokine that regulates Th1 differentiation (for review, see Brombacher et al., 2003; Watford et al., 2004). Besides its importance in host-protective responses to most intracellular infectious microorganisms, the Th1 response is required for the development of autoimmune diseases including arthritis, myocarditis, encephalomyelitis, diabetes, and lupus (Joosten et al., 1997; for review, see Brombacher et al., 2003; Watford et al., 2004).
Recent findings consistently demonstrated that IL-12 induces pain in humans. For instance, 1) patients that received intravenous rhIL-12 therapy for metastatic renal cancer or malignant melanoma presented arthralgias involving primarily the shoulders and fingers (Gollob et al., 2000); 2) patients that received intraperitoneally injected rhIL-12 for Mullerian carcinoma, gastrointestinal primary malignancies, and mesothelioma treatment had headache and abdominal pain (Lenzi et al., 2002); 3) pain and bladder spasms were adverse effects related to the intravesicular treatment with rhIL-12 for cell carcinoma of the bladder (Weiss et al., 2003); and 4) mild to moderate pain at the site of injection has been reported in patients that received peritumoral injection of IL-12-transduced autologous fibroblasts (Kang et al., 2001). However, the mechanisms underlying IL-12-induced pain have not yet been investigated.
At the present time, it is accepted in the literature that a cascade of cytokines constitutes a link between inflammatory stimuli and release of the final mediators that directly sensitize the nociceptors, such as prostanoids and sympathetic amines (Cunha et al., 1992). In rats, inflammatory stimuli induce resident cells to release TNF-, which in turn activates two pathways: 1) TNF- 
IL-6 IL-1
prostaglandins (Cunha et al., 1992), and 2) TNF- cytokine-induced neutrophil chemoattractant 1 (rat IL-8 related chemokine; Lorenzetti et al., 2002) sympathetic amines (Nakamura and Ferreira, 1987; Cunha et al., 1991). The sequential role of cytokines leading to the release of final mediators was further substantiated in rats by Safieh-Garabedian et al. (1997) and, more recently, in mice by Cunha et al. (2005). Furthermore, cytokines may also stimulate the release of other directly acting mediators, such as endothelin (ET) (Verri et al., 2004).
Thus, in the present study we investigated whether the local injection of IL-12 induced mechanical hyperalgesia, as well as the involvement of other cytokines, prostanoid, sympathetic amines, leukotrienes, and endothelin in this process. We found that IL-12 induces mechanical hyperalgesia in a dose- and time-dependent manner, mediated by endothelin acting via the ETB receptor.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Mechanical Hyperalgesic Tests. Hyperalgesia was assessed using two different methods: the constant pressure rat paw and the electronic pressure-meter tests. A different investigator performed each test, prepared the solution, and injected subcutaneously in the hindpaw of rats. Multiple paw treatments with saline did not alter basal reaction time, which was similar to that observed in noninjected paws.
The Constant Pressure Rat Paw Test. Mechanical hyperalgesia was tested in rats as previously described (Ferreira et al., 1978). In this method, a constant pressure of 20 mm Hg (measured using a sphygmomanometer) is applied (via a syringe piston moved by compressed air) to a 15-mm2 area on the dorsal surface of the hindpaw and discontinued when the rat presents a typical "freezing reaction". This reaction is comprised of brief apnea, concomitant with retraction of the head and forepaws, and reduction in the escape movements that animals normally make to free themselves from the position imposed by the experimental situation. Usually, the apnea is associated with successive waves of muscular tremor. For each animal, the latency to the onset of the freezing reaction is measured before administration (zero time) and at different times after administration of the hyperalgesic agents. The intensity of mechanical hyperalgesia is quantified as the reduction in the reaction time, calculated by subtracting the value of the second measurement from the first (Ferreira et al., 1978). Reaction time was 31.9 ± 0.2 s (mean ± S.E.M.; n = 36) before injection of the hyperalgesic agents. A shortened reaction time is prevented by steroidal and nonsteroidal anti-inflammatory drug treatment before an inflammatory stimuli injection (Cunha et al., 1992; Lorenzetti et al., 2002). This method has been used to demonstrate the peripheral effect of morphine (Ferreira et al., 1978; Smith et al., 1982), the contribution of eicosanoids, sympathetic amines, adenosine 3'5' cyclic monophosphate (cAMP), and of cytokines to the development of peripheral inflammatory hyperalgesia (Ferreira and Nakamura, 1979a; Cunha et al., 1992, 2000; Ferreira et al., 1993). These concepts and findings have been extensively confirmed with other methodologies such as formalin-induced flinching and others (Vinegar et al., 1976; Vivancos et al., 2004).
The Electronic Pressure-Meter Test. The paw hyperalgesia was also measured with an electronic pressure-meter. The rats were placed in acrylic cages (12 x 20 x 17 cm high) with a wire grid floor 15 to 30 min before beginning the tests. During this adaptation period, the paws were poked two to three times. Before paw stimulation, the animals should be quiet, without exploratory or toilet movements, and not resting over the paws. In these experiments a pressure-meter, which consisted of a hand-held force transducer adapted with a 0.7-mm2 polypropylene tip (electronic von Frey anesthesiometer; IITC Inc. Life Science Instruments, Woodland Hills, CA), was used. The investigator was trained to apply the polypropylene tip perpendicularly in between the five distal footpads with a gradual increase in pressure. A tilted mirror below the grid provided a clear view of the animal's hindpaw. The test consisted of poking the hindpaw to provoke a flexion reflex followed by a clear flinch response after the paw withdrawal. The electronic pressure-meter automatically recorded the intensity of stimulus when the paw was withdrawn. The stimulation of the paw was repeated until the animal presented three similar measurements (with the difference between the highest and the lowest measurement being no more than 10 g). If the results were inconsistent, the experimenter used another animal (
1:25 animals). The animals were tested before and after treatments, and the results are expressed by the delta reaction force (grams) that was calculated by subtracting the value of the measurements after treatment from that of the first measurement before treatment (Vivancos et al., 2004). The reaction force was 43.6 ± 0.3 g (mean ± S.E.M.; n = 36) before injection of the hyperalgesic agents.
Thermal Test: Hargreaves' Plantar Test. The Hargreaves' test was performed as previously described (Hargreaves et al., 1988), using a standard apparatus (Ugo Basile, Comerio, Italy). The test consists of placing the rat in a transparent acrylic box and applying a thermal radiant stimulus with a mobile infrared heat lamp positioned underneath the targeted hindpaw. The latency of the paw withdrawal response was measured automatically with the help of a photoelectric-sensitive device. The latency of the withdrawal response of each hindpaw was determined before and at 1, 3, and 5 h after IL-12 (3, 10, and 30 ng in 50 µl) or saline (50 µl) i.pl. injection. The intensity of thermal hyperalgesia was expressed as the reduction in the reaction time, calculated by subtracting the value of the post-treatment measurement from the pretreatment.
Protocols. The IL-12-induced mechanical or thermal hyperalgesia was assessed using the following protocols.
Dose- and Time-Dependent Mechanical or Thermal Hyperalgesia Induced by IL-12. To determine whether IL-12 induces mechanical and thermal hyperalgesia, the cytokine (3-30 ng in 50 µl) was injected i.pl., and the nociceptive responses were measured 1, 3, 5, 7, and 24 h later.
Role of Eicosanoids (Prostanoids and Leukotrienes), Sympathetic Mediators, and Morphine Treatment in IL-12-Induced Mechanical Hyperalgesia. The participation of nociceptive mediators in IL-12 (10 ng in 50 µl)-induced mechanical hyperalgesia was determined 1, 3, and 5 h after i.pl. injection of IL-12. The rats were treated with dexamethasone (1 h before, 2.0 mg kg-1 s.c.; Verri et al., 2004), indomethacin [30 min before, 2.5 mg kg-1 s.c., diluted in Tris (2-amino-2-hydroxymethyl-propan-1,3-diol)/HCl, pH 8.0; Cunha et al., 1992], atenolol (30 min before, 1.0 mg kg-1 s.c.; Nakamura and Ferreira, 1987) or 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid, sodium (MK886; 24-h reinforcement dose 1 h before, 1.0 mg kg-1, per oral, diluted in 0.1% methylcellulose in water; Tonussi and Ferreira, 1999). Additionally, it was determined that opioid modulation of IL-12 induced hyperalgesia. Because the peripheral effect of morphine lasts approximately 1 h (Ferreira and Nakamura, 1979b), morphine (3-12 µg in 50 µl i.pl.; Ferreira and Nakamura, 1979b) was injected 4 h after IL-12 administration (10 ng in 50 µl) and evaluated 1 h after its injection. Naloxone (1.0 mg kg-1 i.p.; Ferreira and Nakamura, 1979b) was administrated 30 min before and evaluated 1 h after morphine (6 µg paw-1). The selected doses of dexamethasone, indomethacin, atenolol, MK886, and morphine inhibit carrageenan- or LPS-induced mechanical hyperalgesia (Ferreira and Nakamura, 1979b; Nakamura and Ferreira, 1987; Cunha et al., 1992; Tonussi and Ferreira, 1999; Lorenzetti et al., 2002; Verri et al., 2004), and did not affect the mechanical thresholds of normal animals (data not shown).
Role of TNF- and IL-18 on IL-12-Induced Hyperalgesia and of IL-12 on IL-18-Induced Hyperalgesia. Antiserum to rat TNF- (15 min, 50 µl i.pl.; Ferreira et al., 1993), anti-IL-18 antibody (15 min, 10 µg, 50 µl i.pl.), or control serum (50 µl i.pl.) was administered before IL-12 (10 ng, 50 µl) injection. Furthermore, anti-IL-12 antibody (15 min, 10 ng, 50 µl i.pl.) or control serum (50 µl i.pl.) was administered before IL-18 (40 ng, 50 µl) injection. The effects of the antiserum to rat TNF-, anti-IL-18 antibody and anti-IL-12 antibody (doses described above) upon the TNF- (2.5 pg in 50 µl), IL-18 (40 ng in 50 µl), or IL-12 (10 ng in 50 µl) induced-mechanical hyperalgesia were also determined, respectively. The hyperalgesic responses were measured 1, 3, and 5 h after stimulus i.pl. injection.
Role of Endothelin and Its Receptors in IL-12-Induced Mechanical Hyperalgesia. BQ123 (30 min, 30 nmol in 50 µl i.pl., an ETA receptor antagonist) or BQ788 (30 min, 3-30 nmol in 50 µl i.pl., an ETB receptor antagonist) was injected before IL-12 (10 ng in 50 µl i.pl.) or endothelin-1 (ET-1; 10 pmol in 50 µl i.pl.; Da Cunha et al., 2004) administration. Animals may also be pretreated with indomethacin or atenolol (doses described above) before ET-1 (10 pmol in 50 µl) injection. The hyperalgesic responses were measured 1, 3, and 5 h after IL-12 i.pl. injection.
Drugs, Cytokines, Antibodies, and Antisera. The following materials were obtained from the sources indicated: atenolol (Sigma-Aldrich, St. Louis, MO); human IL-18 (referred to as IL-18; Peprotech Inc., Rocky Hill, NJ), anti-human-IL-18 antibody (referred to as anti-IL-18 antibody; lot 06993 J230, Peprotech Inc., Rocky Hill, NJ); anti-human-IL-12 antibody (referred to as anti-IL-12 antibody; Peprotech Inc.); BQ123 sodium salt (lot A21510
[GenBank]
; Novabiochem, La Jolla, CA); BQ788 sodium salt (lot B32622
[GenBank]
; Calbiochem, La Jolla, CA); dexamethasone (Sigma-Aldrich); human endothelin-1 (referred to as ET-1, American Peptide Company, Sunnyvale, CA); indomethacin (Prodome, Campinas, São Paulo, Brazil); methylcellulose (Sigma-Aldrich); MK886 (lot B39328
[GenBank]
; Calciochem, Darmstadt, Germany); morphine sulfate (Cristália, Itapira, São Paulo, Brazil); naloxone, hydrochloride (Sigma-Aldrich), human IL-12 (referred to as IL-12; lot 95/544), rat recombinant TNF-, sheep antiserum to rat TNF-, and sheep preimmune serum (National Institute of Biological Standards and Control, South Mimms, Hertfordshire, UK), and Tris (Merck, Darmstadt, Germany). The preimmune serum was obtained from the sheep before the immunization procedure. The LPS content of the above materials, as measured in a Limulus Amoebocyte Lysate test, was of the order of 0.25 IU mg-1, which is equivalent to a little over 10-15 g of LPS in a hypernociceptive dose of TNF- (2.5 pg). The threshold hypernociceptive dose of LPS in the above model is 100 ng, i.e., 10-7 g (Ferreira et al., 1993). Therefore, the doses of the hypernociceptive agents used contained amounts of LPS up to eight log10 values less than the threshold hypernociceptive dose of LPS.
|
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Effects of Dexamethasone, Indomethacin, Atenolol, MK886, and Morphine on IL-12-Induced Mechanical Hyperalgesia. The pretreatment of the rats with a glucocorticosteroid (dexamethasone; 2.0 mg kg-1) significantly inhibited IL-12 (10 ng)-induced mechanical hyperalgesia determined by either the constant pressure rat paw test (Fig. 2A) or the electronic pressure-meter test (Fig. 2B). However, the treatment of the animals with a standard cyclooxygenase inhibitor (indomethacin; 2.5 mg kg-1), -adrenergic antagonist (atenolol; 1.0 mg kg-1), or 5-lipoxygenase activating protein inhibitor (MK886; 1.0 mg kg-1) was ineffective in inhibiting IL-12 (10 ng)-induced mechanical hyperalgesia in both tests (Fig. 2, A and B). These results suggest that prostanoids, sympathetic amines, or leukotrienes are not involved in IL-12-induced mechanical hyperalgesia. The fact that dexamethasone inhibited the IL-12-induced hyperalgesia suggests that this cytokine is not directly sensitizing the nociceptor but, rather, that it is acting via the release of glucocorticosteroid-sensitive secondary mediators. Moreover, the treatment with an opioid agonist (morphine, 3, 6, and 12 µg i.pl.) also inhibited in a dose-dependent manner the IL-12 (10 ng)-induced mechanical hyperalgesia, and an opioid antagonist (naloxone, 1.0 mg kg-1; Fig. 2, C and D) prevented the analgesic effect of morphine (6 µg i.pl.).
|
Effects of Antiserum against Rat TNF- or IL-18 Antibody on IL-12-Induced Hyperalgesia and of IL-12 Antibody on IL-18-Induced Hyperalgesia. The pretreatment of rats with antiserum against rat TNF- (50 µl) or anti-IL-18 antibody (10 µg) did not alter IL-12 (10 ng)-induced mechanical hyperalgesia determined by both methods. Furthermore, anti-IL-12 antibody (10 ng) did not alter IL-18 (40 ng)-induced mechanical hyperalgesia (Fig. 3). As expected, the antiserum against rat TNF-, IL-18 antibody, and IL-12 antibody inhibited TNF-- (2.5 pg in 50 µl), IL-18- (40 ng in 50 µl), and IL-12 (10 ng in 50 µl)-induced mechanical hyperalgesia determined by the constant pressure rat paw or the electronic pressure-meter tests (Table 1). These results suggest that IL-12 is not mediating IL-18-induced mechanical hyperalgesia, and neither TNF- nor IL-18 is mediating the IL-12-induced mechanical hyperalgesia.
|
|
Effects of Endothelin ETA and ETB Receptor Antagonists on IL-12-Induced Mechanical Hyperalgesia. As shown in Fig. 4, the ETB receptor antagonist (BQ788; 3-30 nmol) inhibited the IL-12 (10 ng)-induced mechanical hyperalgesia in both tests. The higher dose of BQ788 inhibited the IL-12 hyperalgesia at all selected times using the constant pressure test (Fig. 4A), and in the 3rd and 5th h using the electronic pressure-meter (Fig. 4B). On the other hand, the ETA receptor antagonist (BQ123) did not alter IL-12-induced hyperalgesia. In agreement with these results, in a previous study using these same methods, we demonstrated that ET-1 (10 pmol)-induced mechanical hyperalgesia is also inhibited by an ETB receptor antagonist (BQ788; 10 nmol), although it is not affected by BQ123 (10 nmol). Moreover, neither indomethacin nor atenolol attenuate the ET-1-induced mechanical hyperalgesia in rats (Da Cunha et al., 2004; Verri et al., 2004). Therefore, these results suggest that ET-1 acting on ETB receptors mediates the IL-12-induced mechanical hyperalgesia.
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
), and recently, patients receiving IL-12 as an immune therapy for cancer treatment reported hyperalgesia (Gollob et al., 2000; Kang et al., 2001; Lenzi et al., 2002; Weiss et al., 2003). Therefore, in the present study, we investigated the possible hyperalgesic effect of IL-12 and its pharmacological susceptibility. We report that IL-12 induced significant dose- and time-dependent mechanical hyperalgesia in rats, determined by either constant pressure paw or electronic pressure-meter tests. The IL-12 effects were restricted to the ipsilateral paw (data not shown), and the hyperalgesic dose of IL-12 (10 ng/paw) was at least 50% lower than the local dose of IL-12 used in humans as a vaccine adjuvant (Portielje et al., 2005). The IL-12-induced mechanical hyperalgesia was dose-dependently inhibited by the local administration of morphine, and the nonspecific opioid receptor antagonist blocked this analgesic effect. These results are in line with the observation that opiates directly block hyperalgesia induced by various mediators such as endothelin (Menéndez et al., 2003) and prostaglandins E2 and I2 (Ferreira and Nakamura, 1979b). There is evidence that morphine, besides acting on the central nervous system, has a peripheral effect (Ferreira and Nakamura, 1979b; Smith et al., 1982). It is noteworthy that, differently of mechanical hyperalgesia, IL-12 i.pl. injection did not induce thermal hyperalgesia determined using the Hargreaves test. Similarly, doses of TNF- and IL-1 that induced mechanical hyperalgesia did not induce thermal hyperalgesia (Cunha et al., 1992; Ferreira et al., 1993; Woolf et al., 1997).
The IL-12-induced hyperalgesia was not affected by treatment of the rats with indomethacin, atenolol, and MK886, suggesting that prostanoids, sympathetic amines, and leukotrienes are not involved in the onset of the hyperalgesia induced by this cytokine. It has been demonstrated that hyperalgesia induced by IL-6/IL-1 and by the chemokines cytokine-induced neutrophil chemoattractant 1 or IL-8 is dependent on prostaglandin synthesis and on the release of sympathetic amines, respectively (Cunha et al., 1992, 2000; Ferreira et al., 1993; Lorenzetti et al., 2002). Furthermore, the release of these cytokines is stimulated by TNF-, which is produced in response to inflammatory stimuli, such as carrageenan and LPS (Cunha et al., 1992, 2000; Ferreira et al., 1993; Lorenzetti et al., 2002). It appears that TNF- does not participate in the IL-12-induced hyperalgesia, since it was observed that antiserum against TNF- failed to alter the response. This is consistent with the negative results obtained with indomethacin and atenolol, because these compounds inhibit the hyperalgesia induced by TNF- (Cunha et al., 1992; Ferreira et al., 1993).
Recently, we have shown that the mechanism by which IL-18 induces mechanical hyperalgesia in rats depends on endothelin acting on ETB receptors (Verri et al., 2004). IL-12 and IL-18 have synergic actions in several biological processes including interferon- production, T cell proliferation, and enhancement of cell-mediated cytotoxicity (for review, see Biet et al., 2002). However, the IL-12 hyperalgesia is not dependent on IL-18 since an effective dose of anti-IL-18 antibody did not affect the IL-12-induced process. Further investigating the relation between IL-12 and IL-18, the IL-18-induced mechanical hyperalgesia was not affected by anti-IL-12 antibody, suggesting that the hyperalgesia induced by these cytokines are independent one of each other. The IL-12-induced hyperalgesia was inhibited by dexamethasone. It is important to mention that the patients under IL-12 treatments that reported pain, described in the above clinical study (Gollob et al., 2000; Lenzi et al., 2002; Weiss et al., 2003), were not receiving glucocorticosteroid therapy. Glucocorticosteroids are known inhibitors of the synthesis of eicosanoids (prostaglandins and leukotrienes), proinflammatory cytokines such as TNF-, IL-2, IL-1, IL-6, and IL-18 (for review, see Goulding, 1998; Kodama et al., 2002) and endothelin (Dschietzig et al., 2001). Thus, taking into account the above results indicating that prostanoids, leukotrienes, TNF-, and IL-18 were not involved in the IL-12-induced hyperalgesia, the possible involvement of endothelin and its receptor subtypes was addressed.
It appears that endothelin is involved in the IL-12-induced hyperalgesia, and this effect is mediated via the ETB receptor, since BQ788 (ETB receptor antagonist) but not BQ123 (ETA receptor antagonist) inhibited the IL-12 hyperalgesia. In this context, ET-1 induces time and dose-dependent hyperalgesia, which was inhibited by BQ788, but not by BQ123 (Da Cunha et al., 2004). Furthermore, neither indomethacin nor atenolol affects ET-1-induced hyperalgesia (Ferreira et al., 1989; Da Cunha et al., 2004; Verri et al., 2004). In agreement with our results, ETB receptors mediate phenylbenzoquinone-induced abdominal writhing (Griswold et al., 1999), carrageenan-primed knee joint articular incapacitation (De-Melo et al., 1998), and cytokine- (IL-18) or ET-1-induced mechanical hyperalgesia (Da Cunha et al., 2004; Verri et al., 2004). However, there is also evidence that ETA mediates nociceptive behavior (flinching) induced by direct application of ET-1 on the sciatic nerve (Davar et al., 1998), as well as ET-1-induced thermal hyperalgesia (Menéndez et al., 2003) and ET-1 potentiation of capsaicin-induced nociception (Piovezan et al., 1998). In fact, it has also been reported that the antinociception mediated by endothelin via the ETB receptor is opioid-sensitive (Khodorova et al., 2003). However, other investigators have reported that both ETA and ETB mediate nociception in abdominal writhing (Raffa et al., 1996) and carrageenan-induced mechanical hyperalgesia (Baamonde et al., 2004). These apparent discrepancies could be due to differences in experimental nociceptive models, the dose of endothelin, and time intervals of the nociceptive responses, which might detect the hyperalgesia of different sets of primary sensory neurons.
In conclusion, we demonstrated here for the first time that IL-12 induces mechanical hyperalgesia mediated by endothelin action on ETB receptors in an opioid-sensitive manner in rats. This finding not only highlights a possible adverse effect of IL-12 therapy but also suggests that selective antagonism of the endothelin ETB receptor could be of value to prevent IL-12 therapy-induced clinical pain and hyperalgesia in humans.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
W.A.V. and R.O.M. contributed equally to this work.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: IL, interleukin; Th1, T helper 1; rhIL-12, recombinant human interleukin 12; TNF, tumor necrosis factor; ET, endothelin; i.pl., intraplantar; MK886, 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid (sodium); LPS, lipopolysaccharide; BQ123, cyclo[DTrp-DAsp-Pro-DVal-Leu]; BQ788, N-cys-2,6 dimethylpiperidinocarbonyl-L--methylleucyl-D-1-methoxycarboyl-D-norleucine; ANOVA, analysis of variance.
Address correspondence to: Prof. Dr. Fernando de Queiroz Cunha, Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900-Ribeirão Preto, São Paulo, Brazil. E-mail address: fdqcunha{at}fmrp.usp.br
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Baamonde A, Lastra A, Villazon M, Bordallo J, Hidalgo A, and Menendez L (2004) Involvement of endogenous endothelins in thermal and mechanical inflammatory hyperalgesia in mice. Naunyn-Schmiedeberg's Arch Pharmacol 369: 245-251.[CrossRef][Medline]
Biet F, Locht C, and Kremer L (2002) Immunoregulatory functions of interleukin 18 and its role in defense against bacterial pathogens. J Mol Med 80: 147-162.[CrossRef][Medline]
Brombacher F, Kastelein RA, and Alber G (2003) Novel IL-12 family members shed light on the orchestration of Th1 responses. Trends Immunol 24: 207-212.[CrossRef][Medline]
Cunha FQ, Lorenzetti BB, Poole S, and Ferreira SH (1991) Interleukin-8 as a mediator of sympathetic pain. Br J Pharmacol 104: 765-767.[Medline]
Cunha FQ, Poole S, Lorenzetti BB, and Ferreira SH (1992) The pivotal role of tumor necrosis factor in the development of inflammatory hyperalgesia. Br J Pharmacol 107: 660-664.[Medline]
Cunha JM, Cunha FQ, Poole S, and Ferreira SH (2000) Cytokine-mediated inflammatory hyperalgesia limited by interleukin-1 receptor antagonist. Br J Pharmacol 130: 1418-1424.[CrossRef][Medline]
Cunha TM, Verri WA Jr, Silva JS, Poole S, Cunha FQ, and Ferreira SH (2005) Cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc Natl Acad Sci USA 102: 1755-1760.
Da Cunha JM, Rae GA, Ferreira SH, and Cunha FQ (2004) Endothelins induce ET(B) receptor-mediated mechanical hypernociception in rat hindpaw: roles of cAMP and protein kinase C. Eur J Pharmacol 501: 87-94.[CrossRef][Medline]
Davar G, Hans G, Fareed MU, Sinnott C, and Strichartz G (1998) Behavioral signs of acute pain produced by application of endothelin-1 to rat sciatic nerve. Neuro-report 9: 2279-2283.[Medline]
De-Melo JD, Tonussi CR, D'Orléans-Juste P, and Rae GA (1998) Articular nociception induced by endothelin-1, carrageenan and LPS in naive and previously inflamed knee-joints of the rat: inhibition by endothelin receptor antagonist. Pain 77: 261-270.[CrossRef][Medline]
Dschietzig T, Richter C, Pfannenschmidt G, Bartsch C, Laule M, Baumann G, and Stangl K (2001) Dexamethasone inhibits stimulation of pulmonary endothelins by proinflammatory cytokines: possible involvement of a nuclear factor 
B dependent mechanism. Intensive Care Med 27: 751-756.[CrossRef][Medline]
Ferreira SH, Lorenzetti BB, and Correa FMA (1978) Central and peripheral antialgesic action of aspirin-like drugs. Eur J Pharmacol 53: 39-48.[CrossRef][Medline]
Ferreira SH, Lorenzetti BB, and Poole S (1993) Bradykinin initiates cytokine-mediated inflammatory hyperalgesia. Br J Pharmacol 110: 1227-1231.[Medline]
Ferreira SH and Nakamura MI (1979a) I—Prostaglandin hyperalgesia, a cAMP/Ca2+ dependent process. Prostaglandins 18: 179-190.[CrossRef][Medline]
Ferreira SH and Nakamura MI (1979b) II—Prostaglandin hyperalgesia: the peripheral analgesic activity of morphine, enkephalins and opioid antagonists. Prostaglandins 18: 191-200.[CrossRef][Medline]
Ferreira SH, Romitelli M, and de Nucci G (1989) Endothelin-1 participation in overt and inflammatory pain. J Cardiovasc Pharm 13: S220-S222.
Gollob JA, Mier JW, Veenstra K, McDermott DF, Clancy D, Clancy M, and Atkins MB (2000) Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res 6: 1678-1692.
Goulding NJ (1998) Corticosteroids—a case of mistaken identity? Br J Rheumatol 37: 477-483.
Griswold DE, Douglas SA, Martin LD, Davis TG, Davis L, Ao Z, Luttmann MA, Pullen M, Nambi P, Hay DWP, and Ohlstein EH (1999) Endothelin B receptor modulates inflammatory pain and cutaneous inflammation. Mol Pharmacol 56: 807-812.
Hargreaves K, Dubner R, Brown F, Flores C, and Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32: 77-88.[CrossRef][Medline]
Joosten LA, Lubberts E, Helsen MM, and van den Berg WB (1997) Dual role of IL-12 in early and late stages of murine collagen type II arthritis. J Immunol 159: 4094-4102.[Abstract]
Kang WK, Park C, Yoon HL, Kim WS, Yoon SS, Lee MH, Park K, Kim K, Jeong HS, Kim JA, et al. (2001) Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: outcome of a phase I study. Hum Gene Ther 12: 671-684.[CrossRef][Medline]
Khodorova A, Navarro B, Jouaville LS, Murphy J, Rice FL, Mazurkiewicz JE, Long-Woodward D, Stoffel M, Strichartz GR Yukhananov, and Davar G (2003) Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat Med 9: 1055-1061.[CrossRef][Medline]
Kodama M, Takahashi HK, Iwagaki H, Itoh H, Morichika T, Yoshida A, Yoshioka H, Morimoto Y, Nishibori M, and Tanaka N (2002) Effect of steroids on lipopolysaccharide/interleukin 2-induced interleukin 18 production in peripheral blood mononuclear cells. J Int Med Res 30: 144-160.[Medline]
Lenzi R, Rosenblum M, Verschraegen C, Kudelka AP, Kavanagh JJ, Hicks ME, Lang EA, Nash MA, Levy LB, Garcia ME, et al. (2002) Phase I study of intraperitoneal recombinant human interleukin 12 in patients with Mullerian carcinoma, gastrointestinal primary malignancies and mesothelioma. Clin Cancer Res 8: 3686-3695.
Lorenzetti BB, Veiga FH, Canetti CA, Poole S, Cunha FQ, and Ferreira SH (2002) Cytokine-induced neutrophil chemoattractant 1 (CINC-1) mediates the sympathetic component of inflammatory mechanical hypersensitivity in rats. Eur Cytokine Netw 13: 456-461.[Medline]
Menéndez L, Lastra A, Hidalgo A, and Baamonde A (2003) Nociceptive reaction and thermal hyperalgesia induced by local ET-1 in mice: a behavioural and Fos study. Naunyn-Schmiedeberg's Arch Pharmacol 367: 28-34.[CrossRef][Medline]
Nakamura M and Ferreira SH (1987) A peripheral sympathetic component in inflammatory hyperalgesia. Eur J Pharmacol 135: 145-153.[CrossRef][Medline]
Piovezan AP, D'Orléans-Juste P, Tonussi CR, and Giles RA (1998) Effects of endothelin-1 on capsaicin-induced nociception in mice. Eur J Pharmacol 351: 15-22.[CrossRef][Medline]
Portielje JE, Kruit WH, Eerenberg AJ, Schuler M, Sparreboom A, Lamers CH, Gratama JW, Stoter G, Huber C, and Hack CE (2005) Subcutaneous injection of interleukin 12 induces systemic inflammatory responses in humans: implications for the use of IL-12 as vaccine adjuvant. Cancer Immunol Immunother 54: 37-43.[CrossRef][Medline]
Raffa RB, Schupsky JJ, and Jacoby HI (1996) Endothelin-Induced nociception in mice: Mediation by ETA and ETB receptors. J Pharmacol Exp Ther 276: 647-651.
Safieh-Garabedian B, Kanaan SA, Haddad JJ, Jaoude PA, Jabbur SJ, and Saade NE (1997) Involvement of interleukin-1 beta, nerve growth factor and prostaglandin E2 in endotoxin-induced localized inflammatory hyperalgesia. Br J Pharmacol 121: 1619-1626.[CrossRef][Medline]
Smith TW, Buchan P, Parsons DN, and Wilkinson S (1982) Peripheral antinociceptive effects of N-methyl morphine. Life Sci 31: 1205-1208.[CrossRef][Medline]
Tonussi CR and Ferreira SH (1999) Tumor necrosis factor-alpha mediates carrageenin-induced knee-joint incapacitation and also triggers overt nociception in previously inflamed rat knee-joints. Pain 82: 81-87.[CrossRef][Medline]
Verri WA Jr, Schivo IR, Cunha TM, Liew FY, Ferreira SH, and Cunha FQ (2004) Interleukin-18 induces mechanical hypernociception in rats via endothelin acting on ETB receptors in a morphine-sensitive manner. J Pharmacol Exp Ther 310: 710-717.
Vinegar R, Truax JF, and Selph JL (1976) Quantitative comparison of the analgesic and anti-inflammatory activities of aspirin, phenacetin and acetaminophen in rodents. Eur J Pharmacol 37: 23-30.[CrossRef][Medline]
Vivancos GG, Verri WA Jr, Cunha TM, Schivo IRS, Parada CA, Cunha FQ, and Ferreira SH (2004) An electronic pressure-meter nociception paw test for rats. Braz J Med Biol Res 37: 391-399.[Medline]
Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, and O'Shea JJ (2004) Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev 202: 139-156.[CrossRef][Medline]
Weiss GR, O'Donnell MA, Loughlin K, Zonno K, Laliberte RJ, and Sherman ML (2003) Phase 1 study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder. J Immunother 26: 343-348.
Woolf CJ, Allchorne A, Safieh-Garabedian B, and Poole S (1997) Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha. Br J Pharmacol 121: 417-424.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  D. T. Hamamoto, S. G. Khasabov, D. M. Cain, and D. A. Simone Tumor-Evoked Sensitization of C Nociceptors: A Role for Endothelin J Neurophysiol, October 1, 2008; 100(4): 2300 - 2311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Verri Jr., A. T. G. Guerrero, S. Y. Fukada, D. A. Valerio, T. M. Cunha, D. Xu, S. H. Ferreira, F. Y. Liew, and F. Q. Cunha IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice PNAS, February 19, 2008; 105(7): 2723 - 2728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. A. Verri Jr., T. M. Cunha, C. A. Parada, X.-q. Wei, S. H. Ferreira, F. Y. Liew, and F. Q. Cunha IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-{gamma}, endothelin, and prostaglandin PNAS, June 20, 2006; 103(25): 9721 - 9725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Chichorro, A. R. Zampronio, and G. A. Rae Endothelin ETB Receptor Antagonist Reduces Mechanical Allodynia in Rats with Trigeminal Neuropathic Pain. Experimental Biology and Medicine, June 1, 2006; 231(6): 1136 - 1140. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
