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.