Behavioural evidence supporting a differential role for group I and II metabotropic glutamate receptors in spinal nociceptive transmission
Introduction
Glutamate is the main excitatory transmitter in spinal cord, and is considered to play a key role in spinal nociceptive processing. The actions of glutamate are mediated through activation of the ionotropic receptors (iGluRs), which are ligand-gated cation channels and the metabotropic receptors (mGluRs), which are coupled to G-protein secondary messenger systems. To date, eight genes coding for mGluRs have been cloned, from which more receptors can be generated by alternative splicing. These receptors are divided into three subgroups, based on their sequence similarities and transduction mechanisms (reviewed in Pin and Duvoisin, 1995). Group I mGluRs (mGluR1A, 1B, 1C, 1D and mGluR 5A, 5B) are coupled to phospholipase C (PLC), while group II (GluR2 and mGluR3) and group III (mGluR4A, 4B, mGluR6, mGluR7A, 7B and mGluR8) mGluRs are coupled to inhibition of adenylate cyclase. Expression of mGluR mRNA from all three groups has been identified in rat dorsal horn neurons (Ohishi et al., 1993, Ohishi et al., 1995; Valerio et al., 1997), where they appear to be involved in mediating nociceptive input (Meller et al., 1993; Neugebauer et al., 1994).
Activation of mGluRs can potentiate iGluR-mediated responses in spinal neurons (Bleakman et al., 1992; Bond and Lodge, 1995). This interaction between iGlu and mGlu receptors has been shown to mediate mechanical hyperalgesia (Meller et al., 1993; Boxall et al., 1998) and facilitate formalin-induced nociception (Fisher and Coderre, 1996a). Administration of mGluR agonists can also evoke direct excitation of dorsal horn neurons (Boxall et al., 1996; Budai and Larson, 1998). This action is thought to be responsible for the generation of inflammation evoked hyperexcitability (Neugebauer et al., 1994) associated with hyperalgesia and allodynia. Recent studies indicate that the group I mGluRs may be of particular importance in mediating these effects. Evidence from electrophysiological and behavioural studies has shown that intrathecal administration of the group I agonist (RS)-DHPG induces spontaneous nociceptive behaviours (SNBs) (Fisher and Coderre, 1996b), and hyperalgesia and allodynia in rats (Fisher and Coderre, 1998), which can be blocked by administration of a group I antagonist (Young et al., 1997), and neutralising antibodies raised against mGluR1 and mGluR5 (Fundytus et al., 1998).
Considerably less information is available regarding the role of group II mGluR in nociceptive processing. Evidence from electrophysiological studies has shown that activation of spinal group II mGluRs leads to depression of neuronal responses in vitro (Pook et al., 1992; Jane et al., 1994) and in vivo following inflammation (Stanfa and Dickenson, 1998). However, little is known about the contribution of these receptors to nociceptive behaviour. Spinal administration of (1S,3S)-ACPD has been reported to potentiate the behavioural response to formalin (Fisher and Coderre, 1996a), and induce SNBs (Fisher and Coderre, 1996b), however, the authors suggested this could be due to a non-selective action of (1S,3S)-ACPD on mGluR1.
The aim of the present study was to investigate the role of group I and II mGluRs in mechanical nociceptive processing, in the absence of tissue damage, by examining behavioural responses to mechanical stimuli following administration of selected mGluR drugs. Understanding the functional role of these receptors in spinal nociception may help provide novel targets for the effective treatment of acute pain and in preventing the development of chronic pain states. Some of the data presented here have been published in abstract form (Dolan and Nolan, 1999b).
Section snippets
Methods
Six adult sheep (50–60 kg) were implanted with intrathecal catheters (Portex, UK) at level C3–C6 under general anaesthesia (propofol (Rapinovet, Schering Plough Animal Health, UK) and halothane (Rhone Merieux, UK)) according to the method described by Kyles et al. (1992). Correct positioning of the catheter was confirmed by radiograph. Intrathecal experiments began seven days after surgery. All animals were judged to be clinically normal at the time of the study.
Measurement of mechanical
Results
The pre-drug mean mechanical withdrawal threshold was 11.3±0.3 N (n=60). No difference in baseline thresholds was detected among treatment groups. Treatment with the non-selective mGluR agonist trans-ACPD (5.2–520 nmol) produced a significant dose-dependent increase in mechanical withdrawal thresholds from pre-drug baseline levels, which lasted for between 5–20 min (maximum effect 92±2% increase at 12.5±3 min with 520 nmol trans-ACPD). The increase produced by 520 nmol trans-ACPD was
Discussion
In the present study, trans-ACPD, which acts at both group I and II mGluRs, and L-CCG-I, the group II-selective mGluR agonist both significantly elevated mechanical thresholds recorded in normal animals. These anti-nociceptive effects were blocked by EGLU, a potent antagonist at presynaptic group II mGluRs (Jane et al., 1996). These results, coupled with the failure of the group I-specific antagonist AIDA (Pellicciari et al., 1995), to reduce the agonist-induced effects, suggest that group II
Conclusions
This study demonstrates, for the first time, that intrathecal treatment with a group II mGluR compound is effective in reducing nociceptive behaviour in normal animals. The group II mGluR-mediated anti-nociceptive events, may be explained by depression of spinal glutamate release and/or inhibition of cAMP release. In addition, increased responsiveness induced by a group II mGluR antagonist, suggest a tonic group II mGluR component in spinal cord during normal behaviour. The development of
Acknowledgements
This work was supported by the BBSRC. The authors wish to thank Mr Ian Gibson for his technical assistance.
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