Blockade of the Sigma-1 Receptor Relieves Cognitive and Emotional Impairments Associated to Chronic Osteoarthritis Pain

Abstract

Osteoarthritis is the most common musculoskeletal disease worldwide, often characterized by degradation of the articular cartilage, chronic joint pain and disability. Cognitive dysfunction, anxiety and depression are common comorbidities that impact the quality of life of these patients. In this study, we evaluated the involvement of sigma-1 receptor (σ1R) on the nociceptive, cognitive and emotional alterations associated with chronic osteoarthritis pain. Monosodium iodoacetate (MIA) was injected into the knee of Swiss-albino CD1 mice to induce osteoarthritis pain, which then received a repeated treatment with the σ1R antagonist E-52862 or its vehicle. Nociceptive responses and motor performance were assessed with the von Frey and the Catwalk gait tests. Cognitive alterations were evaluated using the novel object recognition task, anxiety-like behavior with the elevated plus maze and the zero-maze tests, whereas depressive-like responses were determined using the forced swimming test. We also studied the local effect of the σ1R antagonist on cartilage degradation, and its central effects on microglial reactivity in the medial prefrontal cortex. MIA induced mechanical allodynia and gait abnormalities that were prevented by the chronic treatment with the σ1R antagonist. E-52862 also reduced the memory impairment and the depressive-like behavior associated to osteoarthritis pain. Interestingly, the effect of E-52862 on depressive-like behavior was not accompanied by a modification of anxiety-like behavior. The pain-relieving effects of the σ1R antagonist were not due to a local effect on the articular cartilage, since E-52862 treatment did not modify the histological alterations of the knee joints. However, E-52862 induced central effects revealed by a reduction of the cortical microgliosis observed in mice with osteoarthritis pain. These findings show that σ1R antagonism inhibits mechanical hypersensitivity, cognitive deficits and depressive-like states associated with osteoarthritis pain in mice. These effects are associated with central modulation of glial activity but are unrelated to changes in cartilage degradation. Therefore, targeting the σ1R with E-52862 represents a promising pharmacological approach with effects on multiple aspects of chronic osteoarthritis pain that may go beyond the strict inhibition of nociception.

Sigma‐1 receptor modulates neuroinflammation associated with mechanical hypersensitivity and opioid tolerance in a mouse model of osteoarthritis pain

“…E‐52862 also reduced MIA‐induced microgliosis, consistent with the effects of the σ1 receptor antagonist BD1047 attenuating spinal microgliosis in a model of bone cancer pain (Zhu et al, ) and with the high levels of σ1 receptors reported in microglia (Gekker et al, ). Interestingly, E‐52862 was effective in preventing the increased microglial density induced by MIA in supraspinal structures (Carcolé et al, ). In addition, over‐expression of mGlu 5 receptors was completely abolished by E‐52862.…”

The Inhibitory Effects of Slow-Releasing Hydrogen Sulfide Donors in the Mechanical Allodynia, Grip Strength Deficits, and Depressive-Like Behaviors Associated with Chronic Osteoarthritis Pain

“…In the first experiments, baseline responses for the von Frey filaments and grip strength were established. After that, osteoarthritis pain was induced, and animals were tested again on days 19,20,22,25,26,27, and 29 after MIA injection. SS-injected mice were used as controls (six animals per group).…”

“…Microglia are likewise implicated in the progression of chronic pain, and their activation in the supraspinal areas is in part responsible for the molecular neuroplasticity changes associated with chronic pain [21] as well as the emotional disorders accompanying it [3]. Thus, microglial activation has been demonstrated in the medial prefrontal cortex and the hippocampus of animals with depressive-like conducts associated with osteoarthritis or neuropathic pain [18,22] as well as in several brain regions of depressive patients suffering chronic pain [23]. Consequently, the depressive-like behaviors accompanying chronic pain diminished with the administration of microglial inhibitors [24,25].…”

The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?

“…In the case of ICSS and facial expressions of pain, it could be argued that these responses may be self-limited and thus more suitable for testing tonic rather than chronic pain. However, several reports showed that changes in weight bearing, gait alterations, grip strength deficits, and burrowing behavior during other pathological models of pain such as osteoarthritis were maintained for relatively long periods (Chandran et al, 2009;Bryden et al, 2015;Philpott et al, 2017;Carcolé et al, 2019). Therefore, the often-seen recovery of normal values for these outcomes at much earlier time-points than mechanical allodynia may be due to a peculiarity of CFA as a pain model, which does not exert long-lasting functional impairment, rather than to the intrinsic characteristics of these outcomes.…”