Antinociceptive effects of intracerebroventricularly administered P2 purinoceptor agonists in the rat

https://doi.org/10.1016/S0014-2999(01)00947-5Get rights and content

Abstract

We examined the effects of adenosine 5′-triphosphate (ATP) and its analogues administered intracerebroventricularly on nociceptive thresholds in rats. Intracerebroventricular (i.c.v.) administration of ATP (10 and 100 nmol/rat), α,β-methylene-ATP (1–30 nmol/rat) and 2′, 3′-O-(4-benzoylbenzoyl)-ATP (1–30 nmol/rat) dose-dependently elevated the mechanical nociceptive threshold in the paw pressure test. These antinociceptive effects were rapid and short-lasting, peaking at 5 min and disappearing by 20 min after the administration. However, i.c.v. administration of β,γ-methylene-ATP (1–30 nmol/rat) and UTP (10 and 100 nmol/rat) had no significant effects on the mechanical nociceptive threshold. In other tests, i.c.v. administration of α,β-methylene-ATP (10 and 30 nmol/rat) prolonged the thermal nociceptive latency in the hot plate test, but only a higher dose (30 nmol/rat) of α,β-methylene-ATP prolonged the latency in the tail flick test. α,β-Methylene-ATP produced no motor deficit in the inclined plane test. These results suggest that P2X purinoceptors play an inhibitory role in nociception at the supraspinal level.

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

References (53)

  • K. Inoue et al.

    Extracellular adenosine 5′-triphosphate-evoked glutamate release in cultured hippocampal neurons

    Neurosci. Lett.

    (1992)
  • E.J. Kidd et al.

    Evidence for P2X3 receptors in the developing rat brain

    Neuroscience

    (1998)
  • M. Okada et al.

    Interaction between purinoceptor subtypes on hippocampal serotonergic transmission using in vivo microdialysis

    Neuropharmacology

    (1999)
  • J. Sawynok

    Adenosine receptor activation and nociception

    Eur. J. Pharmacol.

    (1998)
  • J. Sawynok et al.

    Peripheral adenosine 5′-triphosphate enhances nociception in the formalin test via activation of a purinergic P2X receptor

    Eur. J. Pharmacol.

    (1997)
  • B. Sperlagh et al.

    ATP acts as fast neurotransmitter in rat habenula: neurochemical and enzymecytochemical evidence

    Neuroscience

    (1995)
  • T.W. Stone

    Physiological roles for adenosine and adenosine 5′-triphosphate in the nervous system

    Neuroscience

    (1981)
  • I. Von Kügelgen et al.

    P2-receptor-mediated inhibition of serotonin release in the rat brain cortex

    Neuropharmacology

    (1997)
  • T.D. White

    Role of adenosine compounds in autonomic neurotransmission

    Pharmacol. Ther.

    (1988)
  • M. Williams et al.

    Purinergic and pyrimidinergic receptors as potential drug targets

    Biochem. Pharmacol.

    (2000)
  • Y. Zhang et al.

    ATP increases extracellular dopamine level through stimulation of P2Y purinoceptors in the rat striatum

    Brain Res.

    (1995)
  • M. Zimmermann

    Ethical guidelines for investigations of experimental pain in conscious animals

    Pain

    (1983)
  • R. Bardoni et al.

    ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord

    J. Neurosci.

    (1997)
  • P.A. Bland-Ward et al.

    Acute nociception mediated by hindpaw P2X receptor activation in the rat

    Br. J. Pharmacol.

    (1997)
  • X. Bo et al.

    Distribution of [3H] α,β-methylene-ATP binding sites in rat brain and spinal cord

    NeuroReport

    (1994)
  • G. Burnstock

    Purinergic mechanisms

    Ann. N. Y. Acad. Sci.

    (1990)
  • Cited by (15)

    • Activation of P2X3 receptors in the cerebrospinal fluid-contacting nucleus neurons reduces formalin-induced pain behavior via PAG in a rat model

      2017, Neuroscience
      Citation Excerpt :

      The P2X3 receptors are not merely expressed on small- and medium-diameter nociceptive DRG neurons but also distributed in the oligomeric configuration of presynaptic ionotropic ATP receptors in rat midbrain (Díaz-Hernández et al., 2001). The activation of P2X3 receptors at supraspinal level exerts an analgesic effect (Fukui et al., 2001, 2006), which is closely linked to the noradrenergic neurons in locus coeruleus (Fukui et al., 2004), crucial components of descending inhibitory systems. Our prior report has demonstrated that the CSF-contacting nucleus might be implicated in the descending inhibitory systems (Liu et al., 2014; Fei et al., 2016).

    • Chapter 9 P2X Receptors in Sensory Neurons

      2006, Current Topics in Membranes
      Citation Excerpt :

      P2X receptors in the brain have been shown to be involved in pain processing, but their activation could result in an analgesic effect. Intracerebroventricular administration of ATP, αβmeATP or 3′‐O‐(4‐benzoyl)benzoyl ATP (BzATP) produces an antinociceptive effect on noxious mechanical stimuli (Fukui et al., 2001), while neither βγmeATP nor UTP affects mechanical sensitivity. It thus appears that brain P2X3 receptors are involved in the antinociception, but further studies are needed to identify the receptor subtypes.

    View all citing articles on Scopus
    View full text