General Papers
GABAB Receptors and Opioid Mechanisms Involved in Homotaurine-Induced Analgesia

https://doi.org/10.1016/S0306-3623(97)00279-6Get rights and content

Abstract

  • 1.

    The involvement of GABAB receptors and opioid mechanisms in homotaurine-induced analgesia has been investigated in current models of nociception by using a GABAB receptor antagonist, morphine, and naloxone. CGP 35348 (50–200 mg/kg IP), a highly selective GABAB antagonist, was administered prior to carrying out a dose–response curve of homotaurine (22.6–445 mg/kg IP) antinociceptive effect in the abdominal constriction (mice) and tail flick (rats) tests.

  • 2.

    The tail flick test was performed in animals pretreated with morphine (0.5 mg/kg SC) and naloxone (1 mg/kg), 15 min before amino acid. Animals treated with saline 10 ml/kg (mice) or 1.25 ml/kg (rats) were included as control for the vehicle used.

  • 3.

    CGP 35348 antagonized the antinociceptive effect of homotaurine in both tests. The range of doses affected by the interaction depended on the test assayed, but it was coincident for the main part of the dose–response curve.

  • 4.

    A subanalgesic dose of morphine potentiated the antinociceptive effect of lower doses of homotaurine in the tail flick test. Naloxone pretreatment inhibited the antinociceptive effect of homotaurine.

  • 5.

    These data imply that GABAB receptor subpopulations and opiate mechanisms are involved in the antinociceptive effect of homotaurine. Because functional relationships have been found between GABAergic and opiate systems in analgesic effects, an interaction of the two mechanisms may be operating in the effects described for homotaurine.

Introduction

It has been shown in previous works that 3-amino-propanesulfonic acid (homotaurine)—chemically related to the amino acid taurine—exerts, at equiactive doses, an antinociceptive effect in chemical (acetic acid inducing abdominal constriction) and thermal (tail flick and tail immersion) nociceptive tests in rodents. This action is mediated through cholinergic mechanisms and can be antagonized by scopolamine sulfate and methyl nitrate (Ruiz et al., 1991; Serrano et al., 1992). It has also been shown that homotaurine may act as an agonist to GABAA receptors (Curtis and Watkins 1965; Enna and Snyder 1975; Giotti et al., 1983), and as partial agonist to GABAB receptors (Wojcik 1986). Because bicuculline pretreatment did not modify the aforementioned antinociceptive action, an involvement of GABAA receptors in this effect of homotaurine can be ruled out (Serrano et al., 1992). The present work aims to evaluate whether GABAB receptors are involved in homotaurine-induced analgesia, by using CGP 35348 (CGP)—a competitive antagonist to these receptors (Bittiger et al., 1990; Olpe et al., 1990). Because it is known that there are interactions between opioid and GABAergic mechanisms, it seems of interest to study the possible involvement of opioid pathways in the analgesic activity of homotaurine, via the responses to subanalgesic doses of morphine and pretreatment with the antagonist naloxone.

Section snippets

Materials and methods

Male Swiss OF1 mice and Wistar rats (mean weight 23 g and 250 g, respectively) from the breeding colony of the Medical School were used in the abdominal constrictions induced by acetic acid (mice) and tail flick (rats) tests. The animals were kept in a 12-hr light/dark cycle and had free access to food and water. At least 1 week before the experiments they were transferred to the laboratories where room temperature was maintained at 22±1°C. All drugs were dissolved in saline and injected in a

Results

The effects of homotaurine after pretreatment with different doses of the GABAB antagonist in the abdominal constriction test are shown in Fig. 1. CGP 35348 lacked antinociceptive effect but it effectively antagonized the dose-dependent antinociceptive effect of the amino acid which was statistically significant from 55.6 mg/kg upward.

The overall evaluation of results concluded that statistically significant differences existed between the amino acid–treated group and the one pretreated with

Discussion

The results obtained appear to confirm an involvement of GABAB receptor subpopulations in the antinociceptive activity of homotaurine. This appears to be an effect exerted in the CNS, but homotaurine, being a zwitterion, might cross the blood–brain barrier to a limited extent. For this reason, some researchers have used its calcium acetyl derivative (acamprosate) to improve CNS passage (Chabenat et al., 1988; Nalpas et al., 1990). In our experience however, CNS distribution occurs to an extent

References (36)

  • I. Asadi et al.

    Effect of 4-aminopiridine (4-AMP) in homotaurine (HT)-induced antinociception

    Meth. Find. Exp. Clin. Pharmac.

    (1996)
  • S.A. Bergman et al.

    GABA agonists enhance morphine and fentanyl antinociception in rabbit tooth pulp and mouse hot plate assays

    Drug Devel. Res.

    (1988)
  • H. Bittiger et al.

    Biochemistry, electrophysiology and pharmacology of a new GABAB antagonistCGP 35348

  • N.G. Bowery

    GABAB receptor pharmacology

    Annu. Rev. Pharmac. Toxicol.

    (1993)
  • C. Chabenat et al.

    Physicochemical, pharmacological and pharmacokinetic study of a new GABAergic compound, calcium acetylhomotaurinate

    Meth. Find. Exp. Clin. Pharmac.

    (1988)
  • D.R. Curtis et al.

    Pharmacological studies upon spinal presynaptic fibers

    Exp. Brain. Res.

    (1966)
  • D.R. Curtis et al.

    The pharmacology of amino acids related to gamma-aminobutyric acid

    Pharmac. Rev.

    (1965)
  • D.A. Cutting et al.

    Alternative approaches to analgesiabaclofen as a model compound

    Br. J. Pharmac.

    (1975)
  • Cited by (9)

    • Congenital taurine deficiency in mice is associated with reduced sensitivity to nociceptive chemical stimulation

      2014, Neuroscience
      Citation Excerpt :

      In mice, by contrast, slc6a6 is expressed in the brain, for example in the hippocampus and the striatum (Sergeeva et al., 2003), which would support central effects, however, still hypothetical, because a comprehensive analysis of slc6a6 expression in brain areas belonging to the pain matrix including the insula has not been done so far. The presently observed taurine-dependent nociceptive sensory deficits have to be distinguished from the antinociceptive effects observed following taurine administration in experimental models of acute (Smullin et al., 1990; Hornfeldt et al., 1992; Silva et al., 1993; Serrano et al., 1998; de Rienzo-Madero et al., 2013) or chronic pain (Pellicer et al., 2007; Hara et al., 2012). These effects likely arise in part from a direct activation of glycine receptors (Pellicer et al., 2007).

    • Taurine in the anterior cingulate cortex diminishes neuropathic nociception: A possible interaction with the glycine<inf>A</inf> receptor

      2007, European Journal of Pain
      Citation Excerpt :

      Besides, it has been proposed as a nociceptive process neuromodulator in the spinal cord with inhibitory properties (Mandel and Pasantes-Morales, 1978; Skilling et al., 1990). In this context, the intrathecal and intraperitoneal administration of taurine has proven to relieve nociceptive stimulation effects (Smullin et al., 1990; Serrano et al., 1998; Legendre, 2001). In the same line of evidence, Belfer et al. (1998) have demonstrated that an increase in taurine uptake as dietary supplementation diminishes chronic nociception measured as autotomy behaviour (AB).

    View all citing articles on Scopus
    View full text