Regular ArticleThe nucleus raphe magnus OFF-cells are involved in diffuse noxious inhibitory controls
Graphical abstract
Introduction
Pain is a complex experience that involves multiple components, including sensory-discriminative, cognitive-evaluative, and affective-emotional ones. In turn, the central nervous system modulates the transmission of nociceptive messages according to the nature of the painful stimulus and behavioral state of the individual (Fields and Basbaum, 2006, Millan, 2002). Thus, a network of descending pathways projecting from the brainstem either inhibits or facilitates the transfer of nociceptive information at the level of the spinal and medullary dorsal horn to higher centers.
One of these naturally activated descending controls is the diffuse noxious inhibitory controls (DNIC). DNIC are very powerful, long-lasting inhibitory controls which have been shown to strongly inhibit spinal (Le Bars, 2002) as well as trigeminal nociceptive neurons (Dallel et al., 1999, Dickenson et al., 1980b). They are triggered by noxious stimuli applied to any part of the body distant from the excitatory receptive field of the neuron under study. DNIC are subserved by a loop with the afferent and efferent pathways running within the ventrolateral quadrant and the dorsolateral funiculus of the spinal cord, respectively (Le Bars, 2002). Nevertheless, that sectioning the spinal cord suppresses DNIC suggests that these controls also involve supraspinal areas (Le Bars, 2002). Thus a region in the caudal medulla, the subnucleus reticularis dorsalis (SRD), was shown to be critically involved in DNIC (Bouhassira et al., 1992). More recently, we demonstrated that the spinoparabrachial (Lapirot et al., 2009) and the hypothalamic dopaminergic descending pathways (Lapirot et al., 2011) contribute to the ascending and descending part, respectively, of the loop subserving DNIC.
The nucleus raphe magnus (NRM), which has been extensively studied in many species, including the rat, is known to play a key role in the descending control of dorsal horn nociceptive processing (Fields and Basbaum, 2006, Heinricher and Ingram, 2008). Its electrical stimulation produces antinociception as well as inhibits the responses of spinal (Fields and Basbaum, 2006) and trigeminal nociceptive neurons (Chiang et al., 1995, Lambert and Zagami, 2009, Meng and Hu, 2000). In addition, the NRM sends direct massive projections to the spinal cord and trigeminal sensory complex via the dorsolateral funiculus (Fields and Basbaum, 2006, Lovick and Wolstencroft, 1983, Mason and Fields, 1989). Such evidences suggest that the NRM contributes to DNIC. Surprisingly, though, experiments designed to test whether the NRM is involved in DNIC have provided conflicting results. On one hand, Morton et al. (1987) showed that, in cats, DNIC are reversibly blocked by a microinjection of local anesthetic into the NRM, a finding consistent with an earlier report of reduced DNIC in rats after electrolytic lesion of this brainstem region (Dickenson et al., 1980a). On the other hand, Bouhassira et al. (1993) failed to find any effect of the ibotenic acid lesion of the NRM area on DNIC. Interestingly, though, a recent fMRI study in humans using cold pressor of the right leg as a conditioning stimulation to reduce heat-induced pain in the left arm suggests the involvement of the periaqueductal gray–rostral ventromedial medulla network into such descending controls of pain (Sprenger et al., 2011). The present experiments were designed to reexamine the issue of the involvement of the NRM in DNIC by using electrophysiological methods in the rat trigeminal system.
Section snippets
Animals
Adult male Sprague–Dawley rats (175–200 g) were obtained from Charles River laboratories (France) and maintained in a light- and temperature controlled environment (lights on 19.00–7.00 h, 22 °C) with food and water ad libitum. All efforts were made to minimize animal suffering and to reduce the number of animals used. Experiments followed the ethical guidelines of the International Association for the Study of Pain (Zimmermann, 1983) and ethical guidelines of the directive 2010/63/UE of the
Results
A total of 37 WDR neurons were recorded within the Sp5O. None of them exhibited spontaneous activity. All had an ipsilateral receptive field that included the intraoral or perioral region. They were sensitive to both innocuous and noxious mechanical stimuli and responded by increasing their firing rate as stimulus intensity increased into the noxious range. When 2-ms-long percutaneous electrical stimuli were applied to the center of their receptive field, responses attributable to peripheral
Discussion
In the electrophysiological paradigm of DNIC, C-fiber-evoked responses of trigeminal WDR neurons are inhibited by a conditioning stimulus, noxious heat of the hindpaw. We show that inactivating the NRM both potentiates the C-fiber-evoked responses and strongly attenuates DNIC of trigeminal WDR neurons. Interestingly, selectively blocking ON-cells with microinjection of the broad-spectrum excitatory amino acid antagonist, kynurenate, into the NRM has no effect on C-fiber-evoked responses and
Acknowledgments
We thank AM Gaydier for the secretarial assistance. This work was supported by funding from Institut National de la Santé et de la Recherche Médicale (INSERM), Université Clermont1 (France), Région Auvergne (France), and CHU Clermont-Ferrand (France). R. C. is supported by a research study grant from the Tunisian Government and CMCU program (PHC-Utique, No. 11G 0802). None of the authors have any conflict of interest to declare.
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2021, Brain ResearchCitation Excerpt :Disruption of RVM function can interfere with the influences exerted by these regions on nociceptive processes, and a variety of cellular mechanisms including glutamatergic, opioid, GABAergic and cannabinoid processes and glia regulate its activity and influences (for review, see Dubner et al., 2014; Ossipov et al., 2014; Chichorro et al., 2017; Chen and Heinricher, 2019). Thereby, by way of its inputs, outputs and intrinsic modulatory processes, the RVM acts as an integral CNS site by which descending controls exert their modulatory influences on spinal and trigeminal nociceptive transmission and pain behaviour and also may contribute to CNS mechanisms by which nociceptive afferent inputs induce DNIC in laboratory animals and conditioned pain modulation in humans (eg, Le Bars et al., 1979; Oliveras et al., 1975; Hu, 1990; Bouhassira et al., 1993; Chiang et al., 1994; Meng et al., 2000; Lambert and Zagami, 2009; Wang et al., 2010; Chebbi et al., 2014; Follansbee et al., 2018; for review, see Fields and Basbaum, 1994; Mason, 2001; Dubner et al., 2014; Ossipov et al., 2014; Chichorro et al., 2017; Chen and Heinricher, 2019; Yarnitsky et al., 2019). In the present study, the RVM neurons were functionally classified in accordance with the well-documented scheme of earlier studies whereby their activity can be linked to the onset of the TF elicited by noxious heating of the tail (eg, Fields et al., 1983, 1995; Ellrich et al., 2001; Schnell et al., 2002; Brink et al., 2012; Salas et al., 2016; Follansbee et al., 2018; Chen and Heinricher, 2019; for review, see Fields and Basbaum, 1994; Mason, 2001; Ossipov et al., 2014; Chichorro et al., 2017).
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2018, Journal of PainCitation Excerpt :Overactivation of the hypothalamic dorsomedial nucleus and amygdala during intense distress (eg, in patients with post-traumatic stress disorder),23,40 who also exhibit abolished CPM17 may thus underlie the pronociceptive response observed among high stress responders in this study. Specifically, CPM is associated with excitation of OFF-cells and inhibition of ON-cells,10,33 and therefore maladaptive or overactivation of the DMN–amygdala–RVM link among high stress responders may underlie their diminished CPM. The finding that CPM was detected only among chronic pain patients with high optimism and low negative affect14 and that more efficient CPM among healthy subjects is associated with reduced stress levels and positive affect4,27,30,53 support this possibility.
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These authors contributed equally to this work.