INTRODUCTION
Pain is the most challenging symptom for patients suffering from chronic inflammatory diseases (Taylor et al., 2010; Walsh and McWilliams, 2014). It is commonly encountered in osteoarthritis, rheumatoid arthritis, psoriasis, contact dermatitis, interstitial cystitis, and host defense or inflammatory bowel disease(Pinho-Ribeiro et al., 2017) and is a major challenge for clinicians(da Silva et al., 2010). Pain impairs patient quality of life and therefore has a major impact on both their physical and mental well-being (Walsh and McWilliams, 2014; Sturgeon et al., 2016). Pharmacological treatments (Smolen et al., 2017) to improve rheumatoid arthritis (RA) or RA-related pain include paracetamol, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and biologic agents, such as anti-tumor necrosis factor (anti-TNF). However, treatments are not consistently effective and/or are associated with strong adverse effects (Højsted and Sjøgren, 2007; Graham et al., 2013; Ioannidis et al., 2013; Boyman et al., 2014; Roda et al., 2016), as evidenced by the current opioid use crisis in North America. More importantly, pain can still be problematic despite optimal control of the inflammatory disease (Taylor et al., 2010; Walsh and McWilliams, 2014; Smolen et al., 2016). Thus, there is considerable interest in finding new strategies to develop effective analgesics to relieve chronic inflammatory-related pain.
Previous studies reported that activation of T-type voltage-gated calcium channels contributes to the nociceptive signaling pathway and showed that these channels are involved in the pathophysiology of pain (Perez-Reyes, 2003; Todorovic and Jevtovic-Todorovic, 2011; Bourinet et al., 2016; Snutch and Zamponi, 2018). T-type calcium channels play an important role in cell excitability and calcium signaling, contributing to a wide variety of physiological functions or pathological situations. In the nervous system, these channels are involved in spontaneous discharges, deep sleep, epilepsy and perception of pain (Perez-Reyes, 2003; Lee et al., 2004; Choi et al., 2007). They belong to a family composed of Cav3.1, Cav3.2 and Cav3.3, of which the Cav3.2 subtype is reported to have a major pronociceptive function (Bourinet et al., 2005; Choi et al., 2007; Todorovic and Jevtovic-Todorovic, 2011; Jacus et al., 2012; Snutch and Zamponi, 2018). Several studies using different chronic pain animal models showed that inhibition of Cav3.2 channels strongly reduced neuropathic pain (For review, see Bourinet et al., 2016), inflammatory pain (Kerckhove et al., 2019) and visceral pain (Francois et al., 2013; Scanzi et al., 2016). The role of Cav3.2 channels in somatic inflammatory chronic pain has been poorly studied and published results are inconsistent: inhibition of Cav3.2 channels either showed (Choi et al., 2007; Kerckhove et al., 2014) or failed to show (Berger et al., 2014; García-Caballero et al., 2014; Smith et al., 2017) an anti-hyperalgesic effect.
The aim of the present study was to clarify the involvement of T-type calcium channels, mainly the Cav3.2 member, in this inflammatory context. Using both genetic and pharmacological strategies in two murine models of subacute and maintained articular inflammation, we confirmed the role of Cav3.2 channels in inflammation and inflammatory-related pain. Our study supports the possibility of considering inhibition of Cav3.2 channels as a new therapeutic perspective in the treatment of inflammation and related pain.