Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing

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Abstract

Group II (mGluR2/3) metabotropic glutamate receptors have been implicated in the mechanisms of persistent pain states. In the present study, the effects of the selective group II metabotropic glutamate receptor agonists LY379268 and LY389795 were evaluated in the formalin test, carrageenan-induced thermal hyperalgesia and mechanical allodynia, and capsaicin-induced mechanical allodynia in rats. The agonists LY379268 and LY389795 produced dose-dependent decreases in formalin-induced behaviors that were antagonized by the mGlu2/3 receptor antagonist LY341495. The group II antagonist LY341495 produced parallel shifts in the LY379268 dose–response curve, consistent with a competitive antagonism. LY379268 decreased formalin-induced behaviors after intracisternal but not intrathecal administration, suggesting primarily a supraspinal site of action. Both LY379268 and LY389795 produced a dose-related reversal of carrageenan-induced thermal hyperalgesia and capsaicin-induced mechanical allodynia, but had no effect on carrageenan-induced mechanical allodynia. Both agonists also increased response latencies in the hot plate test, but were without effect in the tail-flick test. However, both agonists produced motor impairment on the inverted screen at doses that were analgesic. Moreover, tolerance to the analgesic effects of LY379268 developed after 4 days of once-daily repeated administration in the formalin, carrageenan, capsaicin and hot plate tests. The present findings indicate that group II (mGluR2/3) metabotropic glutamate receptors may be involved in the mechanisms of hyperalgesia and allodynia, however tolerance rapidly develops to these effects.

Introduction

Metabotropic glutamate receptors are a family of class III G-protein-coupled receptors comprising eight different subtypes that are referred to as mGlu1-8 (e.g., Pin and Duvoisin, 1995, Hollmann and Heinemann, 1994). The metabotropic glutamate receptor subtypes can be subclassified into three groups by sequence homology and second messenger coupling. Group I (mGlu1 and 5) receptors are positively coupled to inositol phosphate hydrolysis while group II (mGlu2 and 3) and group III (mGlu4, 6, 7, and 8) receptors are negatively coupled to adenylyl cyclase (Pin and Duvoisin, 1995, Conn and Pin, 1997). Moreover, group I receptors are located primarily post-synaptically in the brain whereas group II and III receptors are located primarily presynaptically and function as autoreceptors to decrease the excessive release of glutamate (e.g., Monn et al., 1997, Pin and Duvoisin, 1995, Conn and Pin, 1997, Cochilla and Alford, 1998, Schoepp et al., 1999, Cartmell et al., 2000). Thus, activation of group I receptors generally increases neuronal excitation, while activation of group II or III receptors generally decreases neuronal excitation.

Glutamate is a major excitatory neurotransmitter in primary sensory afferent pathways (e.g., Fundytus, 2001). For example, noxious stimulation, such as the SC administration of formalin, increases the release of glutamate and aspartate in dorsal horn neurons (Skilling et al., 1988). The persistent release of glutamate in pain pathways can lead to the development of central sensitization, characterized by altered responsiveness of dorsal horn and thalamic neurons, expansion of receptive fields, and plasticity of neuronal connections (e.g., Woolf et al., 1994, Coderre, 1993, Urban et al., 1994, Salt and Eaton, 1995). Further, repetitive C-fiber stimulation produces a “wind-up” of dorsal horn neuron activity that is mimicked by the application of l-glutamate (Zieglgansberger and Herz, 1971) and NMDA (King et al., 1988). Blockade of the activation of post-synaptic ionotropic (e.g., Coderre and van Empel, 1994) as well as group I metabotropic receptors, located either post-synaptically in the brain or on peripheral, unmyelinated fibers (e.g., Moroni et al., 1997, Young et al., 1997, Bhave et al., 2001; see also review Varney and Gereau, 2002) has been shown to produce antinociception and decrease central sensitization. On the other hand, agonists at predominantly presynaptic group III metabotropic glutamate receptors, presumably by decreasing glutamate release and neuronal excitability, have also been suggested to produce antinociception and to decrease central sensitization (Fisher and Coderre, 1996, Neugebauer et al., 2000).

In addition, a body of evidence has begun to accumulate suggesting group II metabotropic glutamate receptors play an important role in nociception and central sensitization. Immunoreactivity for mGlu2 and mGlu3 receptors has been detected in the lumbar dorsal horn as well as in dorsal root ganglion cells (Carlton et al., 2001). mGlu3 receptor mRNA was upregulated in the spinal cord of rats after ultraviolet irradiation-induced peripheral inflammation (Boxall et al., 1998) and in the reticular thalamic nucleus and cortex (Neto et al., 2000, Neto et al., 2001) of monoarthritic rats. Administration of the group II mGlu receptor antagonist EGLU into the reticular thalamic nucleus of monoarthric rats reversed ankle bend-induced allodynia in the arthritic joint (Neto and Castro-Lopes, 2000). Electrophysiologically, the spinal administration by microdialysis of mGlu2/3 receptor agonists, including LY379268, attenuated capsaicin-induced central sensitization of spinothalamic tract neurons in primates while having no effect under normal control conditions (Neugebauer et al., 2000). The systemic administration of LY379268 did not affect withdrawal latencies to either mechanical or thermal acute noxious stimuli in normal rats or produce ataxia on the rotarod, but delayed hyperalgesia produced by the intraplantar administration of carrageenan in rats, and also reduced capsaicin-induced hyperalgesia in a warm water tail withdrawal test (Sharpe et al., 2002). Moreover, the mGlu2/3 receptor agonists LY354740, LY379268 and LY389795 attenuated late-phase paw-licking pain behavior in the formalin model of persistent pain and significantly reversed mechanical allodynia in the L5/L6 spinal nerve ligation model of neuropathic pain in rats (Simmons et al., 2002). In the formalin model, the effects of LY354740, LY379268 and LY389795 were dose-dependent and stereoselective and were reversed by the selective mGlu2/3 receptor antagonist LY341495 (Simmons et al., 2002). Thus, mGlu2/3 receptors appear to be involved in persistent pain mechanisms.

One purpose of the present studies was to further characterize the effects of the mGlu2/3 agonists LY379268 and LY389795 (Monn et al., 1996, Monn et al., 1997) in models of persistent pain and C-fiber activation. Thus, dose–response curves were determined for the two agonists, administered alone or concomitantly with the mGlu2/3 receptor antagonist LY341495, in the formalin test in rats. An additional purpose of the present studies was to investigate the potential site(s) of action of mGlu2/3 agonists in producing analgesia. Therefore, the effects of LY379268 administered intrathecally or intracisternally were also determined in the formalin test. In addition, dose–response curves for reversing carrageenan-induced thermal hyperalgesia and mechanical allodynia were determined for LY379238 and LY389795 administered alone, and for LY379268 administered concomitantly with the group II antagonist LY341495. The effectiveness of the mGlu2/3 agonists in reversing mechanical allodynia produced by C-fiber stimulation following the intraplantar administration of capsaicin was also determined. In order to further characterize the effects of mGlu2/3 agonists on nociception produced by acute noxious stimuli, the effects of the two agonists were determined in the hot plate and warm water tail withdrawal tests in rats. The potential motor-impairing effects of the two agonists were determined in the inverted screen test. In addition, since nothing is known as to whether tolerance develops to the analgesic effects of mGlu2/3 agonists with repeated administration, the effects of 4 days of once-daily dosing of LY379268 and LY389795 were determined in the formalin, carrageenan, capsaicin and hot plate tests in rats.

Section snippets

Subjects

Male Sprague–Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) weighing 70–90 g for the carrageenan, tail-flick, hot plate and horizontal screen experiments, 180–220 g for the formalin experiments and 290–325 g for the capsaicin experiments were used. Rats were housed in groups of up to 6 per cage in a large colony room on a 12 h light/dark cycle (lights on 6:00 a.m.), with food and water provided ad libitum. Each animal was used only once. Test sessions were conducted between 8:00 am and 6:00

Formalin test

In animals administered vehicle SC 30 min before formalin, there was an initial peak in the number of events during the first 5-min block after formalin, followed by a decrease in the number of events in the second 5-min block, and subsequently an increase again in blocks 3–9 (Fig. 1, open circles in both panels). When the agonists LY379268 or LY389795 were administered SC 30 min before formalin, they produced dose- and time-related analgesic effects in the formalin test in rats (Fig. 1).

Discussion

The major findings of the present studies are that the mGlu2/3 receptor agonists LY379268 and LY389795 are efficacious after acute doses not only in the formalin test of persistent pain, but also in the carrageenan test of inflammatory pain and the capsaicin test of direct C-fiber activation. In contrast, the mGlu2/3 agonists were not effective in the tail-flick test of acute pain, but were effective in the hot plate test of acute pain. However, the mGlu2/3 receptor agonists were efficacious in

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