A tachykinin NK1 receptor antagonist attenuates the 4β-phorbol-12-myristate-13-acetate-induced nociceptive behaviour in the rat
Introduction
Substance P has been considered to act as an important neurotransmitter implicated in the transmission of nociception. Substance P is contained in small diameter primary sensory fibers and is released into the dorsal horn of the spinal cord following noxious stimulation (Duggan and Hendry, 1986, Tiseo et al., 1990, Ribeiro-da-Silva and Hökfelt, 2000). Substance P preferably binds to and activates tachykinin NK1 receptor, which is concentrated in laminae I of the spinal dorsal horn in a variety of species including human, monkey, and rat (Ding et al., 1999, Yu et al., 1999, Nakaya et al., 1994, Todd et al., 2002).
Selective tachykinin NK1 receptor antagonists have been shown to be active in the second phase of the formalin test, used as a model of inflammatory pain (Chapman and Dickenson, 1993, Gonzales et al., 2000, Henry et al., 1999, Rupniak et al., 1996, Traub, 1996, Yamamoto and Yaksh, 1991). In this test, intraplantar injection of formalin solution elicits nociceptive behaviour, such as paw licking and flinching, accompanied by neuronal excitation in the dorsal horn of the spinal cord. It was reported that pretreatment with PD 156982, a tachykinin NK1 receptor antagonist that poorly penetrates into the central nervous system, had no effect on the nociceptive response (Gonzales et al., 2000). In addition to this, an intrathecal injection of a tachykinin NK1 receptor antagonists CP-96,345 was reported to suppress the second phase response, but an injection of CP-96,344, an inactive isomer of CP-96,345, had no effect (Henry et al., 1999, Yamamoto and Yaksh, 1991). Thus, it is likely that the primary site of analgesic action of tachykinin NK1 receptor antagonists is in the spinal cord.
Taniguchi et al. (1997) reported that an intraplantar injection of 4β-phorbol-12-myristate-13-acetate (PMA), a protein kinase C (PKC) activator, induces paw licking, and flinching behaviour lasted over 45 min in rats. Souza et al. (2002) also showed that, in mice, a PKC activator phorbol-12,13-didecanoate causes long-lasting paw-licking behaviour (∼120 min), which is completely blocked by coinjection of a PKC inhibitor. Mechanisms for this PKC-dependent nociceptive response were discussed and found to be, at least in part, the development of peripheral inflammation. Based on these previous reports, there appears to be similarities between PMA and formalin tests. Both of them cause spontaneous nociceptive behaviour associated with peripheral inflammation. However, the duration of nociceptive response to PMA is longer than that of the second phase of the formalin test, suggesting that different mechanisms may underlie in these two tests.
Current studies were designed to characterize the PMA-induced response as a novel model of inflammatory pain and examine antinociceptive effects of a tachykinin NK1 receptor antagonist, ezlopitant, a quinuclidine-based compound with subnanomolar affinities to the human-type tachykinin NK1 receptors and can penetrate into the central nervous system (Tsuchiya et al., 2002).
Section snippets
Animals
Male Sprague–Dawley rats (150–200 g, Charles River, Yokohama, Japan) were housed on a 12/12-h light/dark cycle with constant temperature (23±1 °C) and relative humidity (55±15%), given food and water ad libitum. The experiments were carried out according to a protocol approved by the Animal Care and Use Committee (ACUC) at the Nagoya Laboratories of Pfizer Global Research and Development. The ACUC found the model to result in transient and modest pain that was minimized wherever possible and
Characterization of response induced by intraplantar injection of PMA
An intraplantar injection of PMA (0.3–10 μg) into the hindpaws of rats dose-dependently increased paw-licking and flinching behaviour (Fig. 1A). The response to PMA initiated at 10–20 min postinjection and lasted up to 120 min. An intraplantar injection of formalin (2% v/v) produced typical biphasic paw-licking and flinching behaviour (Fig. 1B). The second phase response was observed 10 to 30 min after formalin injection.
An injection of PMA at the concentration of higher than 3 μg appeared to
Discussion
In this study, we demonstrated that intraplantar injection of PMA, a PKC activator, caused spontaneous nociceptive behaviour that lasted over 90 min. The development of nocicepetive response to PMA was associated with the formation of edema and erythema in the injected paws. The cellular inflammatory reaction at the site of the PMA injection was observed in our histological studies. Thus, the present results suggest that the nociceptive behaviour in response to PMA is consistent with noxious
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2006, PeptidesCitation Excerpt :Central SP-induced analgesia on thermal and mechanical tests was significantly reduced in morphine-tolerant rats [300]. Ezlopitant, a tachykinin NK-1 antagonist, and resiniferatoxin, a vanilloid VR1 receptor modulator, like morphine block the nociceptive behaviors induced by 4beta-phorbol-12-myristate-13-acetate [1203]. The mammalian tachikinin peptide, hemokinin-1 produced a naloxone-sensitive and NK1-sensitive analgesia at high doses, and an ORL-1 antagonist-sensitive hyperalgesia at low doses [371].