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.