Modification of formalin-induced nociception by different histamine receptor agonists and antagonists

European Neuropsychopharmacology (2007) 17, 122 — 128

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Modification of formalin-induced nociception by different histamine receptor agonists and antagonists Davood Farzin *, Farnaz Nosrati Department of Pharmacology, School of Medicine, Mazandaran University of Medical Sciences, 48168, Sari, Iran Received 4 June 2005; received in revised form 17 February 2006; accepted 7 March 2006

KEYWORDS Pain; Histamine; Formalin test; Mouse

Abstract The present study evaluated the effects of different histamine receptor agonists and antagonists on the nociceptive response in the mouse formalin test. Intracerebroventricular (20—40 Ag/mouse i.c.v.) or subcutaneous (1—10 mg/kg s.c.) injection of HTMT (H1 receptor agonist) elicited a dose-related hyperalgesia in the early and late phases. Conversely, intraperitoneal (20 and 30 mg/kg i.p.) injection of dexchlorpheniramine (H1 receptor antagonist) was antinociceptive in both phases. At a dose ineffective per se, dexchlorpheniramine (10 mg/kg i.p.) antagonized the hyperalgesia induced by HTMT (40 Ag/mouse i.c.v. or 10 mg/kg s.c.). Dimaprit (H2 receptor agonist, 30 mg/kg i.p.) and ranitidine (H2 receptor antagonist, 20 and 40 mg/kg i.p.) reduced the nociceptive responses in the early and late phases. No significant change in the antinociceptive activity was found following the combination of dimaprit (30 mg/kg i.p.) with ranitidine (10 mg/kg i.p.). The antinociceptive effect of dimaprit (30 mg/kg i.p.) was prevented by naloxone (5 mg/kg i.p.) in the early phase or by imetit (H3 receptor agonist, 25 mg/kg i.p.) in both early and late phases. The histamine H3 receptor agonist imetit was hyperalgesic following i.p. administration of 50 mg/kg. Imetitinduced hyperalgesia was completely prevented by treatment with a dose ineffective per se of thioperamide (H3 receptor antagonist, 5 mg/kg i.p.). The results suggest that histamine H1 and H3 receptor activations increase sensitivity to nociceptive stimulus in the formalin test. D 2006 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction Many animal tests have been developed for evaluating of analgesic drugs, including the formalin test of acute

* Corresponding author. Tel.: +98 151 3241031; fax: +98 151 3247106. E-mail address: [email protected] (D. Farzin).

injury-induced pain (Tjølsen et al., 1992). Formalin injections into one of the paws in mice produce a biphasic nociceptive response consisting of a transient early phase followed by a tonic late phase (Hunskaar et al., 1985; Shibata et al., 1989; Teng and Abbott, 1998). The early phase in turn can be attributed to a direct algogenic effect of formalin on the nociceptors, and the late phase to release of local inflammatory mediators responsible for sensitization of primary and spinal sensory

0924-977X/$ - see front matter D 2006 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2006.03.005

Histamine and pain

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neurons and subsequent activation of the nociceptors (Hunskaar and Hole, 1987; Coderre et al., 1993; Puig and Sorkin, 1996). Histamine, one of the local inflammatory mediators is known to be involved both in peripheral and central nociceptive mechanisms (Rang et al., 1991; Hong and Abbott, 1994; Carstens, 1997). The chief site of histamine storage in most tissues is the mast cell, which releases the amine following inflammatory insult. When tissues are injured, stimulated mast cells release histamine resulting in genesis of inflammation and depolarization of nociceptors. Thus, when released at peripheral sites, histamine evokes pain and subsequent release of various pain-related molecules from primary afferent fibers. These peripheral neurological events trigger postsynaptic excitation of secondary neurons in the spinal dorsal horn and signal transduction into the CNS (Baranauskas and Nistri, 1998; Scholz and Woolf, 2002; Yoshida et al., 2005). In the CNS, histamine is a neurotransmitter that participates in the perception of nociception (Prell and Green, 1986; Schwartz et al., 1991a). Although histamine is involved in pathways mediating nociception in animals of various analgesic tests (Glick and Crane, 1978; Shibata et al., 1989; Malmberg-Aiello et al., 1994; Thoburn et al., 1994; Malmberg-Aiello et al., 1998; Parada et al., 2001; Farzin et al., 2002), the role of histamine in formalin-induced nociception is not fully understood. To investigate further this topic, we thought it worthwhile to examine the effects of different histamine receptor agonists and antagonists on formalin-induced nociception.

The nociceptive response in formalin test was measured using a slight modification of the previously described method (Hunskaar et al., 1985). Mice were placed individually in vertical glass cylinders (25 cm in diameter) and after 1 h of accommodation formalin (20 Al of 5% formaldehyde solution in saline) was injected into the dorsal surface of the right hind paw using a microsyringe (Hamilton Co., Reno, NV) with a 27-gauge needle. The amount of time that each mouse spent licking the injected paw was recorded for 50 min in 5-min time intervals. The early phase of the nociceptive response normally peaked 5 min after formalin injection and the late phase 15—50 min after formalin injection, representing the tonic and inflammatory pain responses, respectively (Hunskaar and Hole, 1987).

2.3. Intracerebroventricular injection The intracerebroventricular (i.c.v.) injection was performed during short ether anaesthesia, according to the method of Haley and McCormick (1957), with a constant volume of 5 Al. To ascertain the exact point into which drugs were administered, some mice (at least three mice per each i.c.v. dose of HTMT) were deeply anesthetized and injected i.c.v. with 5 Al of diluted 1:10 Indian ink and their brains were examined macroscopically after sectioning. The experimental protocol was approved by the Research and Ethics Committee of Mazandaran University of Medical Sciences.

2.4. Drugs The following drugs were used: S(+)-dexchlorpheniramine maleate (Research Biochemicals, USA), dimaprit dihydrochloride (ICN Biomedicals, UK), HTMT dimaleate ((6-[2-(4-imidazolyl) ethylamino]N-(4-trifluoromethylphenyl)heptanecarboxamide), Tocris, UK), imetit dihydrobromide (ICN Biomedicals), naloxone hydrochloride (Sigma, UK), ranitidine hydrochloride (Sigma) and thioperamide maleate (ICN Biomedicals). In all cases, the drug doses reported are for the base. The drugs were dissolved in saline, except for HTMT, which was dissolved in a drop of ethanol and then diluted with saline. The vehicle control was ethanol in saline. Drug concentrations were prepared so that the necessary dose could be injected in a volume of 10 ml/kg by intraperitoneal (i.p.) or subcutaneous (s.c.) route. Owing to the reportedly poor ability of trifluoromethyl-phenyl or-toluidide derivatives of histamine to cross the blood—brain barrier (Qiu et al., 1990; Malmberg-Aiello et al.,

2. Experimental procedures 2.1. Animals

Mean time spent licking (sec.)

All experiments were carried out on male Swiss—Webster mice from the Pasteur Institute (Iran), 20—25 g body weight. The animals were housed nine per plastic cage in an animal room maintained at 21 F 2 8C on a 12-h light/dark cycle (lights on 0700—1900 h). Standard laboratory mouse chow (Pars, Iran) and water were available at all times except during the experiments. Each animal was used once only.

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Figure 1 Effects of HTMT (H1 receptor agonist) and dexchlorpheniramine (H1 receptor antagonist) on the nociceptive response in the formalin test. Mice were injected with HTMT (20—40 Ag/mouse i.c.v. or 1—10 mg/kg s.c.), dexchlorpheniramine (10—30 mg/kg i.p.) and saline or vehicle. Thirty minutes later, the mice were injected with formalin and observed for licking of the injected paw for 50 min. The mean time spent licking the injected paw (+ S.E.M.) is reported here for the first 5min (early phase) and from 15 to 50 min (late phase). Data were analyzed by one-way ANOVA followed by Newman—Keuls test. *p b 0.05, **p b 0.01, ***p b 0.001, different from control groups (n = 7—9 mice/group).

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Figure 2 Effect of dexchlorpheniramine on HTMT-induced hyperalgesia in the formalin test. Mice were injected with HTMT (40 Ag/ mouse i.c.v. or 10 mg/kg s.c.), dexchlorpheniramine (10 mg/kg i.p.) and saline or vehicle, 30 min before test. The mean time spent licking the injected paw (+ S.E.M.) is reported here for the first 5 min (early phase) and from 15 to 50 min (late phase). Data were analyzed by one-way ANOVA followed by Newman—Keuls test. *p b 0.05, different from control groups (n = 7—9 mice/group). p b 0.05 between experimental groups at each point were considered statistically significant.

1998), the i.c.v. route of administration was used for the histamine H1 receptor agonist, HTMT (Khan et al., 1986; Qiu et al., 1990). For HTMT, the doses were chosen, on a molar basis, as those at which histamine 2HCl exerts its pharmacologic actions on target cells in central nervous system tissue (Oluyomi and Hart, 1991; MalmbergAiello et al., 1994). The i.p. route of administration was chosen for the histamine H2 or H3 receptor agonists and antagonists, because following peripheral injection, these drugs penetrate the brain where they can subsequently interact with H2 or H3 receptors (Garbarg et al., 1992; Hill et al., 1997). In general, the doses of drugs and pretreatment time were usually those used previously and shown to be pharmacologically active (Oluyomi and Hart, 1991; Malmberg-Aiello et al., 1994; Farzin and Attarzadeh, 2000; Farzin et al., 2002).

3. Results 3.1. Effects of a histamine H1 receptor agonist and antagonist on formalin-induced nociception In Fig. 1, it can be seen that the i.c.v. injection of HTMT (H1 receptor agonist, 40 lg/mouse) increased the duration of licking of the hind paw during the early [ F(3,24) = 4.843, p b 0.0090] and late [ F(3,24) = 5.875, p b 0.0037] phases of the formalin test. Similarly, the s.c. injection of HTMT (5 and 10 mg/kg) also increased the nociceptive response to formalin in the early [ F(3,28) = 7.035, p b 0.0011] and late [ F(3,28) = 7.5, p b 0.0008] phases (Fig. 1). As illustrated in Fig. 1, dexchlorpheniramine (H1 receptor antagonist, 10— 30 Ag/kg i.p.) dose-dependently attenuated the nociceptive response in the early [ F(3,26) = 9.983, p b 0.0001] and late [ F(3,26) = 8.172, p b 0.0005] phases (Fig. 1). Dexchlorpheniramine at a dose ineffective per se (10 mg/kg i.p.) on the duration of licking response was able to antagonize the

2.5. Statistical analysis

Mean time spent licking (Sec.)

The results are presented as means + S.E.M. Data were analyzed only for the early (0—5 min) and late (15—50 min) phases of the formalin test. The mean time spent licking in the late phase is the average of seven 5-min intervals, i.e., the mean (not the total) time spent licking per 5 (not 35) min. The statistical significance of differences between groups was obtained by means of one-way analysis of variance (ANOVA) followed by Newman—Keuls test. Differences with

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Figure 3 Effects of dimaprit (H2 receptor agonist) and ranitidine (H2 receptor antagonist) on the nociceptive response in the formalin test. Mice were injected with dimaprit (10—30 mg/kg i.p.), ranitidine (10—40 mg/kg i.p.) and saline. Thirty minutes later, the mice were injected with formalin and observed for licking of the injected paw for 50 min. The mean time spent licking the injected paw (+ S.E.M.) is reported here for the first 5 min (early phase) and from 15 to 50 min (late phase). Data were analyzed by one-way ANOVA followed by Newman—Keuls test. *p b 0.05, **p b 0.01, ***p b 0.001, different from control groups (n = 7—9 mice/group).

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Histamine and pain

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Figure 4 Effects of ranitidine, naloxone (opioid receptor antagonist) and imetit (H3 receptor agonist) on dimaprit-induced antinociception in the formalin test. Mice were injected with dimaprit (30 mg/kg i.p.), ranitidine (10 mg/kg i.p.), naloxone (5 mg/kg i.p.), imetit (25 mg/kg i.p.) and saline, 30 min before test. The mean time spent licking the injected paw (+ S.E.M.) is reported here for the first 5 min (early phase) and from 15 to 50 min (late phase). Data were analyzed by one-way ANOVA followed by Newman— Keuls test. *p b 0.05, **p b 0.01, ***p b 0.001, different from control groups (n = 7—9 mice/group).

hyperalgesia induced by 40 Ag/mouse i.c.v. or 10 mg/kg s.c. of HTMT (Fig. 2).

3.2. Effects of a histamine H2 receptor agonist and antagonist on formalin-induced nociception Fig. 3 shows the effects of dimaprit (H2 receptor agonist) and ranitidine (H2 receptor antagonist) on the nociceptive response in the formalin test. The i.p. injection of dimaprit (30 mg/kg) attenuated the nociceptive response to formalin in the early [ F(3,26) = 3.222, p b 0.0390] and late [ F(3,26) = 7.055, p b 0.0013] phases. Ranitidine was tested in 3 doses of 10, 20 and 40 mg/kg i.p. As shown in Fig. 3, ranitidine (20 and 40 mg/kg) attenuated the nociceptive response in the early [ F(3,26) = 8.585, p b 0.0004] and late [ F(3,26) = 9.375, p b 0.0002] phases. No significant change in the antinociceptive activity was found following the combination of dimaprit (30 mg/kg i.p.) with ranitidine (10 mg/kg i.p.). However, the antinociceptive effect of dimaprit (30 mg/kg i.p.) was prevented by naloxone (5 mg/kg i.p.)

in the early phase [ F(3,26) = 13.755, p b 0.0001] or by imetit (25 mg/kg i.p.) in both early [ F(3,26) = 20.825, p b 0.0001] and late [ F(3,26) = 8.435, p b 0.0004] phases (Fig. 4).

3.3. Effects of a histamine H3 receptor agonist and antagonist on formalin-induced nociception Treatment of animals with imetit (H3 receptor agonist, 50 mg/kg i.p.) significantly increased the nociceptive response to formalin in the early [ F (2,20) = 4.048, p b 0.0334] and late [ F(2,20) = 5.107, p b 0.0161] phases (Fig. 5). Conversely, thioperamide (H3 receptor antagonist, 10 and 15 mg/kg i.p.) induced an antinociception in the early [ F(3,26) = 14.730, p b 0.0001] and late [ F(2,26) = 6.507, p b 0.0021] phases (Fig. 5). The dose of 5 mg/kg thioperamide i.p., which was ineffective in modifying the nociceptive response, significantly antagonized the hyperalgesic effect of imetit (50 mg/kg i.p.) in the early [ F(3,25) = 9.284, p b 0.0003] and late [ F(3,24) = 19.42, p b 0.0001] phases (Fig. 5).

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Figure 5 Effects of alone or combined administration of imetit (H3 receptor agonist) and thioperamide (H3 receptor antagonist) on the nociceptive response in the formalin test. Mice were injected with imetit (25 and 50 mg/kg i.p.), thioperamide (5—15 mg/kg i.p.) and saline. Thirty minutes later, the mice were injected with formalin and observed for licking of the injected paw for 50 min. The mean time spent licking the injected paw (+ S.E.M.) is reported here for the first 5 min (early phase) and from 15 to 50 min (late phase). Data were analyzed by one-way ANOVA followed by Newman—Keuls test. *p b 0.05, **p b 0.01, ***p b 0.001, different from control groups (n = 7—9 mice/group).

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4. Discussion Histamine is involved in facilitation of the ascending pain transmission or activation of the descending pain suppression system at physiological tissue concentration or higher, respectively (Sakurada et al., 2002, 2003; Yoshida et al., 2005). All three histamine H1, H2 and H3 receptors are found in the dorsal horn, all of which are preferentially localized in superficial laminae I and II (Bouthenet et al., 1988; Traifford et al., 1992; Vizuete et al., 1997). These areas receive nociceptive information from small diameter unmyelinated C primary sensory fibers (PAFs) and medium diameter myelinated AD PAFs, both of which are responsive to chemical, thermal and mechanical noxious stimuli. Histamine H1 receptors have been shown to play a pronociceptive role in the dorsal horn (Bevan, 1999; Millan, 1999; Parada et al., 2001). For example, H1 receptor knock-out mice show a decrease in inflammatory pain response through a loss of the pronociceptive actions of histaminergic pathways in the dorsal horn (Yanai et al., 1998; Mobarakeh et al., 2000) and spinal administration of H1 antagonists elicits antinociception (Olsen et al., 2002). These findings have also been in part confirmed in several studies, showing that formalininduced nociception can be suppressed by H1 antagonists in a dose-dependent manner (Hunskaar and Hole, 1987; Shibata et al., 1989; Parada et al., 2001). In line with this observation, the present data show that both i.c.v. and s.c. injections of the histamine H1 receptor agonist HTMT (Khan et al., 1986; Qiu et al., 1990) induced a dose-dependent hyperalgesia in both phases of nociceptive behavior. Interestingly, the i.p. treatment with the histamine H1 receptor antagonist dexchlorpheniramine prevented from the hyperalgesia induced by HTMT (40 Mg/mouse i.c.v. and 10 mg/kg s.c.) in both phases of nociceptive behavior. This finding suggests that both central and peripheral histamine H1 receptors participate in both phases of the formalin test, as HTMT is unable to cross the blood—brain barrier (Khan et al., 1986; Qiu et al., 1990). Another interesting finding of the present study is that nociception evoked by formalin is blocked by both H2 receptor agonist dimaprit (Durant et al., 1977) and antagonist ranitidine. It is also interesting to note that dimaprit antinociception in the early phase was i.p. naloxone reversible. These findings make it conceivable that the central opioid receptors are implicated in dimaprit-induced antinociception. Acute noxious stimuli enhance the activity of central histaminergic neurons, especially in the periaqueductal grey (PAG) and dorsal horn of the spinal cord, which are rich in both opioid peptides and opioid receptors and may be important sites of action for morphine-like drugs (Gogas and Hough, 1988; Hough and Nalwalk, 1992a,b; Malmberg-Aiello et al., 1994, 1998; Thoburn et al., 1994; Hough et al., 1997; Brown et al., 2001; Millan, 2002). The injection of histamine into the surrounding PAG produces antinociception, which is blocked by the H2 receptor antagonist cimetidine or tiotidine and mimicked by the H2 receptor agonist dimaprit (Glick and Crane, 1978; Thoburn et al., 1994). The PAG-localized H2 receptors are implicated in the antinociception elicited by administration of Mopioids into this structure (Gogas and Hough, 1988; Hough and Nalwalk, 1992a,b; Thoburn et al., 1994). Moreover, injection of H2 antagonists into the PAG inhibits systemic

D. Farzin, F. Nosrati morphine antinociception (Hough and Nalwalk, 1992a; Thoburn et al., 1994). These findings suggest that the PAG-localized H2 receptors can activate descending inhibitory tone by cerebral M-opioidergic mechanisms. However, our results do not distinguish H2 receptor involvement in formalin-induced nociception, as the combination of dimaprit and ranitidine produced no evidence for this concept. This discrepancy may be due to the lack of selectivity of the used compounds at the H2 receptors level, because most H2 ligands have some affinity for all subtypes of histamine receptors (Hill et al., 1997; Schwartz et al., 1991b). This is in agreement with previous observations by Hough et al. (1997), who reported that ranitidine, burimamide and norburimamide show similar analgesic potencies, but have H2 blocking properties that vary by more than 1000-fold, and by Netti et al. (1988), who showed that the analgesic properties of ranitidine and cimetidine are not shared by the H2 receptor antagonist famotidine. For dimaprit, it is also possible that the observed antinociception may be due to a non-specific effect of high dose. Although dimaprit is thought to be a selective histamine H2 receptor agonist, it binds to H3 receptors in the brain and antagonizes H3 receptor activation (Arrang et al., 1983). Therefore, it may be that dimaprit increases the pain threshold by such a mechanism, as the histamine H3 receptor agonist imetit (Garbarg et al., 1992) prevented from dimaprit antinociception in both phases of nociceptive behavior. Further experiments are needed to verify the above hypothesis and also to explain how H2-blockade can induce antinociception. In the present study, the histamine H3 receptor agonist imetit (Garbarg et al., 1992) increased the sensitivity of mice to formalin in both early and late phases, while the histamine H3 receptor antagonist thioperamide (Hew et al., 1990) was antinociceptive. Moreover, the hyperalgesia evoked by imetit was blocked by thioperamide at a dose ineffective per se. The antagonistic interaction between imetit and thioperamide in the early phase formalin response suggests that the supraspinal H3 receptors are implicated in imetit-induced hyperalgesia. The reversal of imetit hyperalgesia in the late phase by thioperamide also suggests that the effect of imetit is at least partly mediated by stimulation of peripheral H3 receptors. The histamine H3 receptor mediates presynaptic inhibition of neurotransmitter release on a variety of neuronal tissues in the central and peripheral nervous systems (Schwartz et al., 1990, 1991a,b). Histamine levels in the central nervous system are increased by peripheral administration of the selective histamine H3 receptor antagonist thioperamide, but reduced by the selective histamine H3 receptor agonist imetit, also given peripherally (Arrang et al., 1987; Garbarg et al., 1992). The increase in central concentrations of histamine provoked by treatment with H3 receptor antagonists is associated with antinociception, whereas the reduction of histamine release elicited by H3 receptor agonists enhances nociception (Malmberg et al., 1997; Suh et al., 1999). These findings combined with our present results in the early phase suggest that histamine H3 receptor mechanism plays an important role in the modulation of central perception of nociceptive stimuli. In line with this possibility, the hyperalgesic activity of imetit during the late phase results from a stimulation of nociceptive message transmission via an action at peripheral sites. This hypothesis is partly supported by the results that H3

Histamine and pain receptor stimulation inhibits mast cell depletion (Dimitriadou et al., 1994, 1997) and that mast cell depletion inhibits the late phase of the formalin test (Shibata et al., 1989). In conclusion, the present results suggest that histamine H1 and H3 receptor activations increase sensitivity to nociceptive stimuli in the early and late phases of the formalin test. Further experiments are needed to determine the precise H2 receptor mechanism.

Acknowledgements This work was supported by a grant from the Mazandaran University of Medical Sciences.

References Arrang, J.M., Garbarg, M., Schwartz, J.C., 1983. Autoinhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 302, 832 – 837. Arrang, J.M., Garbarg, M., Schwartz, J.C., 1987. Autoinhibition of histamine synthesis mediated by H3-receptors. Neuroscience 23, 149 – 157. Baranauskas, G., Nistri, A., 1998. Sensitization of pain pathways in the spinal cord: cellular mechanisms. Prog. Neurobiol. 54, 349 – 365. Bevan, S., 1999. Nociceptive peripheral neurons: cellular properties. In: Wall, P.D., Melzack, R. (Eds.), Textbook of Pain, 4th edition. Churchill Livingston, Edinburgh, pp. 85 – 103. Bouthenet, M.L., Ruat, M., Sales, M., Garbarg, M., Schwartz, J.C., 1988. A detailed mapping of histamine H1-receptors in guineapig central nervous system established by autoradiography with [125I]iodobolpyramine. Neuroscience 26, 553 – 600. Brown, R.E., Stevens, D.R., Haas, H.L., 2001. The physiology of brain histamine. Prog. Neurobiol. 63, 637 – 672. Carstens, E., 1997. Response of rat spinal dorsal horn neurons to intracutaneous microinjection of histamine, capsaicin and other irritants. J. Neurophysiol. 77, 2499 – 2514. Coderre, T.J., Fundytus, M.E., McKenna, J.E., Dalal, S., Melzack, R., 1993. The formalin test: a validation of the weighted-scores method of behavioural pain rating. Pain 54, 43 – 50. Dimitriadou, V., Rouleau, A., Dam Trung Tuong, M., Newlands, G.J.F., Miller, H.R.P., Luffau, G., Schwartz, J.C., Garbarg, M., 1994. Functional relationship between mast cells and C-sensitive nerve fibers evidenced by histamine H3 receptor modulation in rat lung and spleen. Clin. Sci. 87, 151 – 163. Dimitriadou, V., Rouleau, A., Dam Trung Tuong, M., Newlands, G.J.F., Miller, H.R.P., Luffau, G., Schwartz, J.C., Garbarg, M., 1997. Functional relationship between sensory nerve fibers and mast cells of dura mater in normal and inflammatory conditions. Neuroscience 77, 829 – 840. Durant, G.J., Ganellin, C.R., Parsons, M.E., 1977. Dimaprit [S-[3(N,N-dimethylamino)propyl]isothiourea] a highly specific histamine H2 receptor agonist: Part 2. Structure activity considerations. Agents Actions 7, 39 – 43. Farzin, D., Attarzadeh, M., 2000. Influence of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rat. Eur. J. Pharmacol. 404, 169 – 174. Farzin, D., Asghari, L., Nowrouzi, M., 2002. Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists. Pharmacol. Biochem. Behav. 72, 751 – 760. Garbarg, M., Arrang, J.M., Rouleau, A., Lingneau, X., Dam Trung Tuong, M., Schwartz, J.C., Ganellin, C.R., 1992. S-[2-(4-Imidazolyl)ethyl]isothiourea, a highly specific and potent histamine H3 receptor agonist. J. Pharmacol. Exp. Ther. 263, 304 – 310.

127 Glick, S.D., Crane, L.A., 1978. Opiate-like and abstinence-like effects of intracerebral histamine administration in rats. Nature 273, 547 – 549. Gogas, K.R., Hough, L.B., 1988. Effects of zolantidine, a brainpenetrating H2-receptor antagonist, on naloxone-sensitive and naloxone-resistant analgesia. Neuropharmacology 27, 357 – 362. Haley, T.J., McCormick, W.G., 1957. Pharmacological effects produced by intracerebral injections of drugs in the conscious mouse. Br. J. Pharmacol. Chemother. 12, 12 – 15. Hew, R.W., Hodgkinson, C.R., Hill, S.J., 1990. Characterization of histamine H3 receptors in guinea-pig ileum with H3 selective ligands. Br. J. Pharmacol. 101, 621 – 624. Hill, S.J., Ganellin, C.R., Timmerman, H., Schwartz, J.C., Shankley, N.P., Young, J.M., Schunack, W., Levi, R., Haas, H.L., 1997. International union of pharmacology: XIII. Classification of histamine receptors. Pharmacol. Rev. 49, 253 – 278. Hong, Y., Abbott, F.V., 1994. Behavioural effects of intraplantar injection of inflammatory mediators in the rat. Neuroscience 63, 827 – 836. Hough, L.B., Nalwalk, J.W., 1992a. Modulation of morphine antinociception by antagonism of H2 receptors in the periaqueductal grey. Brain Res. 588, 58 – 66. Hough, L.B., Nalwalk, J.W., 1992b. Inhibition of morphine antinociception by centrally administered histamine H2 receptor antagonists. Eur. J. Pharmacol. 215, 69 – 74. Hough, L.B., Nalwalk, J.W., Li, B.Y., Leurs, R., Menge, W.M.P.B., Timmerman, H., Carlile, M.E., Cioffi, C., Wentland, M., 1997. Novel qualitative structure-activity relationships for the antinociceptive actions of H2 antagonists, H3 antagonists and derivatives. J. Pharmacol. Exp. Ther. 283, 1534 – 1543. Hunskaar, S., Hole, K., 1987. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30, 103 – 114. Hunskaar, S., Fasmer, O.B., Hole, K., 1985. Formalin test in mice, a useful technique for evaluating mild analgesics. J. Neurosci. Methods 14, 69 – 76. Khan, M.M., Marr-Leisy, D., Verlander, M.S., Bristow, M.R., Strober, S., Goodman, M., Melmon, K.L., 1986. The effects of derivatives of histamine on natural suppressor cells. J. Immunol. 137, 308 – 314. Malmberg, A.B., Chen, C., Tonegawa, S., Basbaum, A.I., 1997. Preserved acute pain and reduced neuropathic pain in mice lacking PKCg. Science 278, 279 – 283. Malmberg-Aiello, P., Lamberti, C., Ghelardini, C., Giotti, A., Bartolini, A., 1994. Role of histamine in rodent antinociception. Br. J. Pharmacol. 111, 1269 – 1279. Malmberg-Aiello, P., Lamberti, C., Ipponi, A., Bartolini, A., Schunack, W., 1998. Evidence for hypernociception induction following histamine H1 receptor activation in rodents. Life Sci. 63, 463 – 476. Millan, M.J., 1999. The induction of pain: an integrative review. Prog. Neurobiol. 57, 1 – 164. Millan, M.J., 2002. Descending control of pain. Prog. Neurobiol. 66, 355 – 474. Mobarakeh, J.I., Sakurada, S., Katsuyama, S., Kutsuwa, M., Kuramasu, A., Lin, Z.Y., Watanabe, T., Hashimoto, Y., Watanabe, T., Yanai, K., 2000. Role of histamine H1 receptor in pain perception: a study of the receptor gene knockout mice. Eur. J. Pharmacol. 391, 81 – 89. Netti, C., Guidobono, F., Sibilia, V., Villa, I., Cazzamalli, E., Pecile, A., 1988. Central effects of histamine H2-receptor agonists and antagonists on nociception in the rat. Agents Actions 23, 247 – 249. Olsen, U.B., Elorp, C.T., Ingvardsen, B.K., Jo/rgensen, T.K., Lundbaek, J.A., Thomsen, C., Hansen, A.J., 2002. ReN 1869, a novel tricyclic antihistamine, is active against neurogenic pain and inflammation. Eur. J. Pharmacol. 435, 43 – 57.

128 Oluyomi, A.O., Hart, S.L., 1991. Involvement of histamine in naloxone-resistant and naloxone-sensitive models of swim stress-induced antinociception in the mouse. Neuropharmacology 30, 1021 – 1027. Parada, C.A., Tambeli, C.H., Cunha, F.Q., Ferreira, S.H., 2001. The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception. Neuroscience 102, 937 – 944. Prell, G.D., Green, J.P., 1986. Histamine as a neuroregulator. Annu. Rev. Neurosci. 9, 209 – 254. Puig, S., Sorkin, L.S., 1996. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase2 activity. Pain 64, 345 – 355. Qiu, R., Melmon, K.L., Khan, M.M., 1990. Effects of histaminetrifluoromethyl-toluidide derivative (HTMT) on intracellular calcium in human lymphocytes. J. Pharmacol. Exp. Ther. 253, 1245 – 1252. Rang, H.P., Bevan, S., Dray, A., 1991. Chemical activation of nociceptive peripheral neurones. Br. Med. Bull. 47, 534 – 548. Sakurada, S., Orito, T., Sakurada, C., Sato, T., Hayashi, T., Mobarakeh, J.I., Yanai, K., Onodera, K., Watanabe, T., Sakurada, T., 2002. Possible involvement of tachykinin NK1 and NMDA receptors in histamine-induced hyperalgesia in mice. Eur. J. Pharmacol. 434, 29 – 34. Sakurada, S., Orito, T., Furuta, S., Watanabe, H., Mobarakeh, J.I., Yanai, K., Watanabe, T., Sato, T., Onodera, K., Sakurada, C., Sakurada, T., 2003. Intrathecal histamine induced spinally mediated behavioral responses through tachykinin NK1 receptors. Pharmacol. Biochem. Behav. 74, 487 – 493. Scholz, J., Woolf, C.J., 2002. Can we conquer pain? Nat. Neurosci. 5, 1062 – 1067. Schwartz, J.C., Arrang, J.M., Garbarg, M., Pollard, H., 1990. A third histamine receptor subtype: characterization, localization and function of the H3-receptor. Agents Actions 30, 13 – 23. Schwartz, J.C., Arrang, J.M., Garbarg, M., Pollard, H., Ruat, M., 1991a. Histaminergic transmission in the mammalian brain. Physiol. Rev. 71, 1 – 51. Schwartz, J.C., Arrang, J.M., Bouthenet, M.L., Garbarg, M., Pollard, H., Ruat, M., 1991b. Histamine receptors in brain. In: Uvna ¨s, B.

D. Farzin, F. Nosrati (Ed.), Handbook of Experimental Pharmacology, Histamine and Histamine Antagonists. Springer-Verlag, Berlin, pp. 191 – 242. Shibata, M., Ohkubo, T., Takahashi, H., Inoki, R., 1989. Modified formalin test: characteristic biphasic pain response. Pain 38, 347 – 352. Suh, H.W., Song, D.K., Choi, Y.S., Kim, Y.H., 1999. Effects of intrathecally injected histamine receptor antagonists on the antinociception induced by morphine, beta-endorphine, and U50,488H administered intrathecally in the mouse. Neuropeptides 30, 485 – 490. Teng, C.J., Abbott, F.V., 1998. The formalin test: a dose-response analysis at three developmental stages. Pain 76, 337 – 347. Thoburn, K.K., Hough, L.B., Nalwalk, J.W., Mischler, S.A., 1994. Histamine-induced modulation of nociceptive response. Pain 58, 29 – 37. Tjølsen, A., Berge, O.G., Hunskaar, S., Rosland, J.H., Hole, K., 1992. The formalin test: an evaluation of the method. Pain 51, 5 – 17. Traifford, E., Pollard, H., Moreau, J., Ruat, M., Schwartz, J.C., Martinez-Mir, M.I., Palacios, J.M., 1992. Pharmacological characterization and autoradiographic localization of histamine H2 receptors in human brain identified with [125I]iodoaminopotentidine. J. Neurochem. 59, 290 – 299. Vizuete, M.L., Traiffort, E., Bouthenet, M.L., Ruat, M., Souil, E., Tardivel-Lacombe, J., Schwartz, J.C., 1997. Detailed mapping of the histamine H2 receptor and its gene transcripts in guinea-pig brain. Neuroscience 80, 321 – 343. Yanai, K., Son, L.Z., Endou, M., Sakurai, E., Nakagawasai, O., Tadano, T., Kisara, K., Inoue, I., Watanabe, T., Watanabe, T., 1998. Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience 87, 479 – 487. Yoshida, A., Mobarakeh, J.I., Sakurai, E., Sakurada, S., Orito, T., Kuramasu, A., Kato, M., Yanai, K., 2005. Intrathecally-administered histamine facilitates nociception through tachykinin NK1 and histamine H1 receptors: a study in histidine decarboxylase gene knockout mice. Eur. J. Pharmacol. 522, 55 – 62.