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.

Keywords: cognition; depression; medial prefrontal cortex; microglia; osteoarthritis; pain; sigma-1 receptor.

FIGURE 1

Repeated treatment with E-52862 reversed mechanical hypersensitivity associated to osteoarthritis pain. (A) Mice received an intra-knee injection of MIA or saline and were treated with vehicle or E-52862 (20 mg/kg) from day 1 until the end of the experiment (day 25). Mechanical thresholds were assessed with the von Frey under basal conditions and on days 5 and 19 after the intra-articular injection, and gait was analyzed with the Catwalk test on days 6 and 12. (B) MIA-injected mice treated with vehicle showed a decrease on mechanical thresholds that was reversed in E-52862-treated mice. Catwalk analysis revealed a decrease of the ratio (right hind/left hind paws) of print area (C) and maximal contact area (D) in mice injected with MIA and treated with vehicle. This alteration was reversed in mice receiving E-52862. Swing (E) and duty cycle (F) were not significantly altered by the intra-knee injection. Data are expressed as mean ± SEM (n = 6–8 animals per group). ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001 vs. Saline-vehicle, ^##p < 0.01, ^###p < 0.001 for MIA-vehicle vs. MIA-E-52862 (3-way repeated measures ANOVA followed by Fisher Least Significant Difference test). MIA, monosodium iodoacetate; SEM, standard error of the mean; RH, right hind; LH, left hind.

FIGURE 2

Histological knee alterations in mice injected with MIA were not prevented by the chronic treatment with E-52862. Ipsilateral knees of saline and MIA mice were obtained 29 days after intra-articular injection in mice receiving vehicle or E-52862 treatment. (A) Medial and lateral sides of the joints are represented, showing the femur condyle (above) and the tibial plateau (below). (B) The injection of MIA produced cartilage degeneration revealed by an increased OARSI score. Treatment with E-52862 (20 mg/kg, twice daily during 25 days) did not prevent the joint damage. (C) The semiquantitative scoring system for joint histopathology. The scores for each image are (first value represents femur condyle and second value represents tibial plateau): (a) 1, 0.5; (b) 0.5, 0; (c) 2, 5; (d) 2, 5; (e) 2, 0.5; (f) 0, 0.5; (g) 3, 6; (h) 2, 3. Data are expressed as the mean ± SEM (n = 5–7 animals per group). Scale bar: 100 μm. ^∗∗∗p < 0.001 for saline vs. MIA (2-way ANOVA). MIA, monosodium iodoacetate; SEM, standard error of the mean.

FIGURE 3

Acute and chronic treatments with E-52862 improved the cognitive deficits induced by MIA injection. (A) Saline or MIA-injected mice treated with vehicle or E-52862 (20 mg/kg, twice daily during 25 days) were evaluated for recognition memory 15 days after the intra-knee injection in the novel object recognition test (NORT). (B) Mice with osteoarthritis pain treated with vehicle showed decreased discrimination index indicating a memory impairment. Acute and chronic treatment with E-52862 reversed the cognitive deficits induced by MIA. (C) Animals revealed similar total exploration times regardless of the surgery or the treatment. Data are expressed as mean ± SEM (n = 6–8 animals per group). ^∗p < 0.05, ^∗∗∗p < 0.001 vs. MIA-vehicle (1-way ANOVA followed by Fisher least significant difference test). MIA, monosodium iodoacetate; SEM, standard error of the mean.

FIGURE 4

E-52862 treatment reduced depressive-like behavior, but not anxiety-like responses associated with chronic osteoarthritis pain. (A) Emotional manifestations of osteoarthritis pain were assessed in saline- or MIA-injected mice after repeated administration with vehicle or E-52862 (20 mg/kg, twice daily during 25 days) to saline or MIA-injected mice. Anxiety-like behavior was evaluated on day 11 after the intra-knee injection with the elevated plus maze (EPM), and at day 21 in the zero-maze (Z-maze), while depressive-like behavior was determined in the forced-swimming test (FST) on day 25. The latency to enter in the open arms (B), and the percentage of time (C) and entries (D) to the open arms of the EPM showed no significant differences between groups. At day 21, no significant differences were observed in the latency to the open quadrants of the zero-maze (E), whereas mice injected with MIA and treated with vehicle spent less time in the open parts (F). This increase on late anxiety-like behavior was not modified by E-52862 treatment. (G) Mice with osteoarthritis pain receiving vehicle showed increased immobility time, which was reversed by E-52862 treatment. Data are expressed as mean ± SEM (n = 6–8 animals per group). For (D): ^∗∗∗p < 0.001 for saline vs. MIA (two-way ANOVA). For (E): ^∗p < 0.05 for saline – vehicle vs. MIA – vehicle, ^##p < 0.01 for MIA – vehicle vs. MIA – E-52862 (two-way ANOVA). MIA, monosodium iodoacetate; SEM, standard error of the mean.

FIGURE 5

E-52862 decreased pain-induced microgliosis in the medial prefrontal cortex. Microglial cells were detected in the prelimbic and infralimbic areas of the medial prefrontal cortex (mPFC) of saline and MIA injected mice after the repeated treatment with vehicle or the σ1R antagonist E-52862 (20 mg/kg, twice daily during 25 days). Mice with osteoarthritis pain treated with vehicle showed an increased density of microglial cells in the prelimbic (A) and the infralimbic areas (D). This microgliosis was normalized by the treatment with E-52862 (A,D). MIA-injected mice revealed larger perimeters of the soma of microglial cells in the infralimbic (E), but not in the prelimbic area (B). Treatment with E-52862 did not modify this alteration (E). (C,F) Representative images of all groups are shown. Data are expressed as the mean ± SEM (n = 7 animals per group). Scale bar: 100 μm. ^∗p < 0.05, ^∗∗∗p < 0.001 for saline vs. MIA, ^##p < 0.01 for vehicle vs. E-52862 (two-way ANOVA). MIA, monosodium iodoacetate; SEM, standard error of the mean.