Enhanced pronociception by amygdaloid group I metabotropic glutamate receptors in nerve-injured animals
Introduction
The amygdala is a major player in emotions (Phelps and LeDoux, 2005). It also receives ascending nociceptive signals (Bernard et al., 1996) and it has efferent projections to structures that are involved in pain modulation (e.g., Rizvi et al., 1991, Van Bockstaele et al., 1996). These findings, together with chemical or electrical stimulation and lesion studies (see below), indicate that the amygdala has a role in pain modulation. Interestingly, the role is a dual one varying from antinociception (Helmstetter and Bellgowan, 1993, Helmstetter et al., 1998, Manning and Mayer, 1995, McGaraughty and Heinricher, 2002, Mena et al., 1995, Nandigama and Borszcz, 2003) to pronociception (Greenwood-Van Meerveld et al., 2001, Manning, 1998, Quin et al., 2003).
Sustained nociception produces synaptic plasticity in the amygdala. This has been shown in electrophysiological recordings performed in animals with inflammatory pain (Neugebauer et al., 2004, Neugebauer, 2006) and in control animals following tetanic stimulation of the parabrachial nucleus that relays nociceptive inputs to the amygdala (Lopez de Armentia and Sah, 2007). Peripheral nerve injuries may cause chronic neuropathic pain that is associated with plastic changes in pain-mediating (Woolf and Salter, 2006) and -regulating (Almeida et al., 2006, Pertovaara, 2000, Porreca et al., 2002) pathways. Recent studies indicate that peripheral nerve injury induces neural plasticity in the amygdala, as shown by increased postsynaptic currents evoked by ascending inputs (Ikeda et al., 2007) and generation of new amygdala neurons (Gonçalves et al., 2008). These findings still leave open whether the pain regulatory role of the amygdala is changed by peripheral nerve injury.
In the present study we test a hypothesis that peripheral nerve injury influences pain regulation by the amygdala. Partial support for this hypothesis is provided by a recent finding showing that amygdaloid activation by glutamate suppressed presumably antinociceptive neurons in the noradrenergic locus coeruleus of nerve-injured animals (Viisanen and Pertovaara, 2007). To test further this hypothesis, we determined whether administration of glutamatergic compounds into the amygdala has a differential influence on discharge rates of putative pain-regulatory neurons in the rostroventromedial medulla (RVM) of nerve-injured versus sham-operated animals. For this purpose, we recorded discharge rates of presumably pronociceptive ON-cells and antinociceptive OFF-cells in the RVM (Fields et al., 2006). Moreover, we assessed whether the effect by amygdaloid administration of a glutamatergic compound on affective pain-related behavior in an aversive place-conditioning test is changed following peripheral nerve injury.
Section snippets
Materials and methods
The experiments were performed in adult, male Hannover-Wistar rats weighing 180–190 g at the beginning of the experiment (Harlan, Horst, the Netherlands). The experimental protocol was accepted by the Institutional Ethics Committee and the experiments were performed according to the guidelines of the European Communities Council Directive of 24 November 1986 (86/609/EEC). All efforts were made to minimize animal suffering and to use only the number of animals necessary to produce reliable
Response characteristics of RVM neurons
Spontaneous activity of RVM ON-cells was significantly influenced by SNI (F1,131 = 4.79, P = 0.030; 2-w-ANOVA) and postoperative time point of testing (F1,131 = 4.19, P = 0.043; 2-w-ANOVA). Post hoc tests indicated that the spontaneous discharge rate of ON-cells was increased in the SNI group 1 week after nerve injury, while 8 weeks following injury it was reduced to the same level as in sham controls (Fig. 3a). Spontaneous activity of RVM OFF-cells was influenced by postoperative time point of testing
Discussion
In the present study, amygdaloid administration of DHPG, an mGluR1/5 agonist, increased the discharge rate of presumably pronociceptive ON-cells in the RVM of nerve-injured but not sham-operated animals. This enhanced pronociceptive effect was at least due to action on the amygdaloid mGluR1, since DHPG, an agonist of the mGluR1 and mGluR5, but not CHPG, an mGluR5 agonist, increased discharge rates of RVM ON-cells and this DHPG-induced effect was reversed by CPCCOEt, an mGluR1 antagonist.
Conclusions
Present results indicate that group I mGluRs in the amygdala may promote nociception in nerve-injured animals. This was shown by increased excitation of pronociceptive RVM ON-cells following amygdaloid administration of a group I mGluR agonist in neuropathic animals. Since the amygdala has a key role in processing emotions and since the administration of glutamatergic compounds into the amygdala potentially mimics emotional activation of the amygdala, it may be proposed that activation of the
Acknowledgments
This work was supported by the Academy of Finland and the Sigrid Jusélius Foundation, Helsinki, Finland, and the Portuguese Foundation for Science and Technology and the Gulbenkian Foundation, Lisbon, Portugal.
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