Antinociceptive effects of intracerebroventricularly administered P2 purinoceptor agonists in the rat
Introduction
In addition to diverse intracellular roles, extracellular adenosine 5′-triphosphate (ATP) has been established as a neurotransmitter or neuromodulater in both the peripheral White, 1988, Inomata et al., 1991 and central nervous systems Edwards et al., 1992, Ueno et al., 1992, Jo and Schlichter, 1999. ATP is contained in synaptic vesicles and co-released with noradrenaline, acethylcholine or other substances Sneddon et al., 1982, Stone, 1981, Jo and Schlichter, 1999, and then acts on specific receptors, designated as P2 purinoceptors, on the cell surface. P2 purinoceptors are classified into two subfamilies, ionotropic P2X receptors and metabotropic P2Y receptors, on the basis of their structures and signal transduction systems (Ralevic and Burnstock, 1998). cDNAs for seven subtypes of P2X receptors and five subtypes of P2Y receptors have been cloned as P2 purinoceptors expressed in mammalian cells.
Recent studies suggest the involvement of ATP and its receptors in peripheral and spinal nociceptive transmission Kennedy and Leff, 1995, Burnstock, 1996. It was reported that mRNA of the P2X3 purinoceptor in the dorsal root ganglia is selectively expressed in capsaicin-sensitive, small diameter afferent neurons, which are probably associated with nociception (Chen et al., 1995). Cook et al. (1997) demonstrated that nociceptive, but not non-nociceptive, sensory neurons had P2X3 immunoreactivity in their nerve endings and cell bodies. In electrophysiological studies, ATP and α,β-methylene-ATP, a P2X receptor agonist, evoked inward currents in capsaicin-sensitive, small diameter dorsal root ganglion neurons (Ueno et al., 1999) and spinal dorsal horn neurons Bardoni et al., 1997, Ping et al., 1998. Furthermore, in vivo studies have provided a body of evidence of the role of P2 purinoceptors at peripheral and spinal sites in nociception. Peripheral administration of ATP and α,β-methylene-ATP have been shown to cause nociceptive responses Bland-Ward and Humphrey, 1997, Dowd et al., 1998 and facilitate formalin-induced responses (Sawynok and Reid, 1997). Intrathecal administration of α,β-methylene-ATP induced thermal hyperalgesia, which was blocked by P2 purinoceptor antagonists Driessen et al., 1994, Tsuda et al., 1999. These observations strongly support the idea that ATP plays a crucial role in facilitating pain transmission at peripheral and spinal sites, probably via the P2X purinoceptor.
At supraspinal sites, several studies have shown that ATP and its analogues induced fast synaptic currents in the cultured neurons derived from the hippocampus (Inoue et al., 1992) and nucleus of the solitary trace (Ueno et al., 1992) as well as in the slices from the rat medial habenula Edwards et al., 1997, Sperlagh et al., 1995. In addition, it was reported that ATP enhances or inhibits the release of some neurotransmitters including noradrenaline Von Kügelgen et al., 1994, Koch et al., 1997b, dopamine Koch et al., 1997a, Zhang et al., 1995, serotonin Von Kügelgen et al., 1997, Okada et al., 1999 and glutamate Koizumi and Inoue, 1997, Inoue, 1998. Thus, ATP is considered to play various physiological roles at supraspinal sites. However, little is known about the involvement of supraspinal ATP and its receptors in nociception. The goal of the present study was to determine the effects of ATP analogues administered i.c.v. on mechanical and thermal nociception and to assess whether the effects observed can be ascribed to a particular type or subtype of P2 purinoceptors through the use of type- or subtype-selective agonists.
Section snippets
Animals and surgical procedures
All experiments using male Sprague–Dawley rats weighing 220–280 g followed the ethical guidelines for investigations of experimental pain in conscious animals (Zimmermann, 1983). Animals were kept at a constant ambient temperature (24±1°C) under a 12-h light/dark cycle with free access to food and water. Under pentobarbital (50 mg/kg, i.p.) anesthesia, a stainless steel guide cannula (o.d. 0.7 mm) was stereotaxically (P 0.8, L 1.5, H 2.0) implanted on the right side according to the atlast of
Effects of i.c.v. administration of ATP and its analogues on mechanical nociceptive threshold in the paw pressure test
I.c.v. administration of ATP (100 nmol/rat) slightly, but significantly, elevated the mechanical nociceptive threshold to the paw-pressure stimulation (Fig. 1A). I.c.v. administration of α,β-methylene-ATP (1–30 nmol/rat) produced a dose-dependent elevation of the mechanical nociceptive threshold (Fig. 1B). A significant elevation of the threshold was observed at 5 min after i.c.v. administration of α,β-methylene-ATP at doses of 10 and 30 nmol/rat (156±12% and 173±12% of control, respectively)
Discussion
The findings of the present study showed that i.c.v. administration of ATP to rats elevated the mechanical nociceptive threshold in the paw pressure test. A greater elevation was observed when α,β-methylene-ATP or Bz-ATP was administered i.c.v., whereas β,γ-methylene-ATP and UTP had no significant effects on mechanical nociception. I.c.v. administration of α,β-methylene-ATP at doses showing antinociceptive effects had no effects on motor function in the inclined plane test, indicating that the
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