Osteoarthritis Pain in Old Mice Aggravates Neuroinflammation and Frailty: The Positive Effect of Morphine Treatment

Abstract

Knee osteoarthritis is a common cause of pain and disability in old subjects. Pain may predispose to the development of frailty. Studies on mechanisms underlying pain in osteoarthritis models during aging are lacking. In this work, we used the monosodium iodoacetate model of osteoarthritis in adult (11-week-old) and old (20-month-old) C57BL/6J mice to compare hypersensitivity, locomotion, neuroinflammation, and the effects of morphine treatment. After osteoarthritis induction in adult and old mice, weight-bearing asymmetry, mechanical allodynia, and thermal hyperalgesia similarly developed, while locomotion and frailty were more affected in old than in adult animals. When behavioral deficits were present, the animals were treated for 7 days with morphine. This opioid counteracts the behavioral alterations and the frailty index worsening both in adult and old mice. To address the mechanisms that underlie pain, we evaluated neuroinflammatory markers and proinflammatory cytokine expression in the sciatic nerve, DRGs, and spinal cord. Overexpression of cytokines and glia markers were present in osteoarthritis adult and old mice, but the activation was qualitatively and quantitatively more evident in aged mice. Morphine was able to counteract neuroinflammation in both age groups. We demonstrate that old mice are more vulnerable to pain’s detrimental effects, but prompt treatment is successful at mitigating these effects.

Prokineticin System Is a Pharmacological Target to Counteract Pain and Its Comorbid Mood Alterations in an Osteoarthritis Murine Model

“…In this regard, MIA mice display allodynia in the ipsilateral paw and are characterized by a neuroinflammatory condition in the sciatic nerve and spinal cord. As we already observed in the MIA OA model at earlier time points, i.e., 14 [41] and 21 [49] days after MIA injection, we found a neuroinflammatory condition affecting the sciatic nerve and the spinal cord 28 days after OA induction as well. In both tissues, but particularly in the sciatic nerve, we observed a marked upregulation of PK2 and PKR1, accompanied by high levels of IL-1β and IL-6.…”

“…Under general anesthesia (i.p. 60 mg/kg sodium pentobarbital, Sigma-Aldrich, Milan, Italy), MIA mice were treated with a single intra-articular (IA) injection of 1 mg of MIA in a volume of 10 μL of saline solution (NaCl 0.9%) [ 40 , 41 ]. CTR mice received an IA injection of saline solution (10 µL).…”

“…The test was conducted in both contra- (data not shown) and ipsi-lateral paw. The test started with a value of force below the detection threshold and continued with an increased force until the animal removed its paw [ 41 , 43 ]. Response to mechanical stimuli (Paw Withdrawal Threshold, PWT) was expressed in grams (g).…”

“…Rotarod test: locomotor activity was evaluated by an accelerating protocol: 4–20 rpm in 600 s. The test was considered finished when the animal fell down (fall time), arrived at the cut-off (600 s) or if the animal stood still and completed three full passive rotations (last rotation time) [ 41 ].…”

Alleviating effect of lycorine on CFA‑induced arthritic pain via inhibition of spinal inflammation and oxidative stress

“…Lower pain thresholds and punctate hyperalgesia in the area of concern are thus often observed in patients with OA (8). Patients with advanced OA often experience widespread pain at the OA joint and even in the whole leg (9). In an OA animal model, mechanical hyperalgesia and allodynia are also observed (5).…”