GABA, but not opioids, mediates the anti-hyperalgesic effects of 5-HT7 receptor activation in rats suffering from neuropathic pain
Highlights
► 5-HT7 receptor agonists reduced mechanical hyperalgesia in sciatic nerve-ligated rats. ► Intrathecal bicuculline blocked 5-HT7R-mediated antihyperalgesia in neuropathic rats. ► 5-HT7R-mediated antihyperalgesia is unaffected by spinal opioid receptors blockade. ► Both spinal and supraspinal processes contributed to 5-HT7R-mediated antihyperalgesia.
Introduction
Neuropathic pain is a major problem for clinicians because of the limited efficacy of drugs currently used for its alleviation (Finnerup et al., 2010). Thus, the development of new therapeutic tools is of particular importance in order to relieve pain in medical practice. In this regard, monoaminergic neurotransmission is still a relevant target as shown by the recent development of innovative antinociceptive drugs (Finnerup et al., 2010; Riemsma et al., 2011). Among monoamines, serotonin (5-hydroxytryptamine, 5-HT) is of particular interest because it can mediate both antinociceptive and pronociceptive actions at the spinal level (Bardin, 2011; Kayser et al., 2010a; Millan, 2002; Suzuki et al., 2004). This bidirectional effect depends not only on the type, duration, intensity of the nociceptive stimulus, the location and extent of the injury, but also on the multiplicity of 5-HT receptors (Bardin, 2011; Kayser et al., 2010a, Kayser et al., 2010b; Suzuki et al., 2004). As a consequence, the understanding of the actual role of 5-HT in pain control requires the knowledge of the functional implication of the different 5-HT receptor types.
One of the most recently identified 5-HT receptors among those that may play a role in pain processing is the 5-HT7R. Indeed, several lines of evidence support the idea that this receptor is most probably involved in pain control at peripheral, spinal and/or supraspinal levels (Amaya-Castellanos et al., 2011; Brenchat et al., 2009, 2010, 2012; Dogrul and Seyrek, 2006; Dogrul et al., 2009; Meuser et al., 2002; Rocha-Gonzalez et al., 2005; Yanarates et al., 2010). Its mRNA is expressed in dorsal root and trigeminal ganglia (Pierce et al., 1996; Terron et al., 2001). In the dorsal horn of the spinal cord, 5-HT7R is present in laminae I–II and III on A∂ and C primary afferent fibers, on peptidergic interneurons and on glial cells (Doly et al., 2005; Neumaier et al., 2001). Its expression at the supraspinal level in regions related to pain control and/or perception, such as cortical areas, thalamic nuclei and several nuclei in midbrain, pons and medulla, is also consistent with its implication in pain control (Harte et al., 2005; Neumaier et al., 2001). As a whole, available data point to an antinociceptive effect of central 5-HT7R activation, whereas peripheral 5-HT7R would mediate pronociceptive effects of 5-HT (Brenchat et al., 2009, 2010, 2012; Dogrul and Seyrek, 2006; Dogrul et al., 2009; Meuser et al., 2002; Rocha-Gonzalez et al., 2005; Yanarates et al., 2010). In conditions involving central sensitization, the overall effect of systemically administered 5-HT7R agonists seems to be analgesic (Brenchat et al., 2009, 2010, 2012).
In order to further investigate mechanisms underlying 5-HT7R-mediated modulation of neuropathic pain, we used validated rat models which consist of chronic constriction injury to the sciatic nerve (CCI-SN; Bennett and Xie, 1988) or the infraorbital nerve (Vos et al., 1994). Mechanical and thermal nociceptive tests, immunohistochemical labeling of c-Fos expression (used as neuronal activity marker) and qRT-PCR determinations of mRNAs encoding pro-inflammatory cytokines were used to characterize the effects of 5-HT7R stimulation (mainly by the selective agonist E-55888; Brenchat et al., 2010) in these models. On the other hand, because 5-HT7R activation causes neuronal excitation (Leopoldo et al., 2011; Matthys et al., 2012) and interferes with opioidergic and GABAergic mechanisms (Dogrul and Seyrek, 2006; Tokarski et al., 2011), pharmacological experiments were carried out to assess whether 5-HT7R-mediated excitation of inhibitory opioidergic and/or GABAergic interneurons could underlie the effects of 5-HT7R agonists.
Section snippets
Animals
Adult male Sprague-Dawley rats (175–200 g on arrival) were purchased from Charles River (L'Arbresle, France). They were housed in a controlled environment (22 ± 1 °C, 60% relative humidity, 12:12 h light–dark cycle, lights on at 7:00 a.m.) with food and water available ad libitum. Animals were allowed to habituate to these housing facilities without any handling for at least 1 week before surgery. In all cases, experiments were performed in conformity with the Guidelines of the Committee for
Effects of acute systemic administration of 5-HT7R agonists in CCI-SN rats
Two weeks after surgery, most of CCI-SN rats (80%) exhibited clear-cut hyperalgesia to hindpaw pressure on the ipsilateral side. Randall–Selitto test allowed determination of paw withdrawal threshold values of 217 ± 3 g before ligature and 141 ± 5 g (−35%, p < 0.05) two weeks after surgery (means ± S.E.M. of 72 rats). Similarly, vocalization threshold value was 466 ± 7 g before ligature and 293 ± 9 g (−37%, p < 0.05) two weeks later. No modifications of response thresholds were observed in sham
Discussion
In this study, we investigated how 5-HT7R contribute to neuropathic pain modulation by using potent 5-HT7R antagonist (SB-269970) and/or agonists (MSD-5a, AS-19, E-55888) in rats with unilateral ligations of the sciatic nerve or the infraorbital nerve. Marked reductions in mechanical and thermal hypersensitivity were observed in CCI-SN rats treated with 5-HT7R agonists, in agreement with previous reports showing anti-nociceptive effects of 5-HT7R stimulation in various chronic pain models with
Acknowledgments
This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie (UPMC, Paris 6) and Institut UPSA de la Douleur. Florent Viguier received fellowship supports from the Fondation pour la Recherche Médicale (FRM), the Société Française de Pharmacologie et de Thérapeutique (SFPT) and UPSA, and Benoît Michot received fellowship grants from the French Ministry of Research and SFPT during performance of these studies.
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