Introduction
With an estimated 300 million sufferers, osteoarthritis (OA) is a
leading cause of chronic pain and disability worldwide [1, 2]. In
the absence of disease-modifying therapy, current treatment options aim
to relieve pain and preserve joint function. Although several (classes
of) medications are available for pain relief in OA (e.g., non-steroidal
anti-inflammatory drugs - NSAIDs, paracetamol/acetaminophen, tramadol,
duloxetine), treatment outcomes are often unsatisfactory due to limited
efficacy and/or side effects and toxicities mostly associated with
chronic use [1, 2]. Comorbidities that frequently occur in patients
with OA (such as depression) [1] make treatment even more difficult.
OA is characterized by cartilage damage and loss, subchondral bone
remodeling and joint inflammation [1, 3]. During the pathological
process, structural and inflammatory cells produce numerous mediators
that can activate and/or sensitize nociceptors in the joint, causing
pain and pain hypersensitivity. Nerve growth factor (NGF) appears to
play a central role in the pathogenesis of OA pain. In addition to
activation and sensitization of nociceptors, it contributes to the
development of central sensitization by increasing the expression of
several neurotransmitters and modulators (including substance P and
brain-derived neurotrophic factor, BDNF) in the dorsal root ganglia
(DRG) and spinal cord [4, 5]. Cytokines (e.g., IL-1β, TNF-α) and
reactive oxidative species are also involved (directly or indirectly) in
the development of sensitization at different levels of the pain pathway
[6-8]. Sensitization is considered a key process in the
chronification of pain. It is responsible for hyperreactivity to
non-noxious or mild noxious stimuli (allodynia and hyperalgesia,
respectively) and makes the treatment of chronic pain challenging [1,
3, 9]. Targeting pain pathway sensitization is considered crucial for
improving pain management in OA [1].
Vortioxetine is a relatively new antidepressant with improved
tolerability profile and cognition-enhancing effects [10]. Its
potential to relieve chronic pain has recently been demonstrated in
animals (constriction and chemotherapy-induced neuropathy) [11, 12]
and humans (burning mouth syndrome) [13]. Vortioxetine’s unique
mechanism of action combines inhibition of the serotonin (5-HT)-reuptake
transporter (SERT) and direct action on several 5-HT receptor subtypes
that are important for pain modulation [10]. We have previously
demonstrated that in addition to serotonergic,
adrenergic/cholinergic/cannabinoid/adenosine receptors are also involved
in its antinociceptive action in an inflammatory pain model
characterized by pain pathway sensitization [14]. Recent evidence
also shows that vortioxetine can reduce pro-inflammatory cytokine levels
(including IL-1β, TNF-α) and exert antioxidant effects [15, 16]. We
therefore hypothesized that vortioxetine may be effective against OA
pain by acting on multiple factors involved in sensitization of pain
pathway.
To test this hypothesis, we used a rat model of knee OA induced by
intra-articular injection of the chondrocyte glycolytic inhibitor
monoiodoacetate (MIA) that shares important pathophysiological and
manifestation features with OA in humans [6, 17]. During the 28-day
treatment protocol, we observed pain-related behaviors and after
euthanasia, we determined the expression of pain-related mediators (NGF,
IL-1β, TNF-α, BDNF, substance P) and oxidative stress parameters in the
affected knee, corresponding DRGs and spinal cord, where relevant.
Duloxetine, the only antidepressant currently recommended for the
treatment of OA pain [2] was studied in parallel as a reference
drug. Along the way, we monitored whether there were sex differences in
the characteristics of the disease model and in the effects of
antidepressants.