Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain

Abstract

BackgroundThe exact mechanism of knee osteoarthritis (OA)-associated pain is unclear, whereas mixed evidence of inflammatory pain and neuropathic pain has been noted. We aimed to investigate pain-related sensory innervation in a monoiodoacetate (MIA)-induced model of OA.MethodsSixty of seventy female Sprague Dawley rats of six week-old underwent intra-articular MIA and fluorogold (FG) retrograde neurotracer injection into their right (ipsilateral) knee, while their left knees were treated with FG in saline as a control (contralateral knee). Other rats were treated with FG only bilaterally, and used as controls. Rats were evaluated for tactile allodynia using von Frey hairs. Proinflammatory mediators in the knee soft tissues, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and nerve growth factor (NGF), were quantified using ELISAs to evaluate inflammation in the knee after 1, 4, 7,14,21, and 28 days post injection:. Dorsal root ganglia (DRG) were immunostained for three molecules after 7,14,21, and 28 days post injection: calcitonin gene-related peptide (CGRP), a marker of inflammatory pain; and activating transcription factor-3 (ATF3) and growth associated protein-43 (GAP43), as markers for nerve injury and regenerating axons. The distribution of microglia in the spinal cord were also evaluated, because they have been reported to increase in neuropathic pain states. These evaluations were performed up to 28 days postinjection. P < 0.05 was considered significant.ResultsProgressive tactile allodynia and elevated cytokine concentrations were observed in ipsilateral knees. CGRP-immunoreactive (-ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner. Significant proliferation of microglia were found with time in the ipsilateral dorsal horn.ConclusionsPain-related characteristics in a MIA-induced rat OA model can originate from an inflammatory pain state induced by the local inflammation initiated by inflammatory cytokines, and that state will be followed by gradual initiation of neuronal injury, which may induce the neuropathic pain state.

Anti-Inflammation Effects of Low Intensity Laser Therapy on Monosodium Iodoacetate-induced Osteoarthritis in Rats

“…These inflammatory mediators further contribute to OA pathogenesis by increasing cartilage degradation and inducing hyperalgesia. TNF-α activates sensory neurons directly via its receptors and initiates a cascade of inflammatory reactions through the production of IL (IL-1β, IL-6, IL-7, IL-17, and IL-18) [8][9][10] .…”

Unrestricted Weight Bearing as a Method for Assessment of Nociceptive Behavior in a Model of Tibiofemoral Osteoarthritis in Rats

“…administration of monosodium iodoacetate (MIA) in rats is a validated chemical model used to investigate OA. MIA, when injected through the patellar tendon in the hind limb of rodents, displays multiple components of disease progression and symptoms similar to human OA and induces significant nociceptive behavior [9][10][11] albeit with a different time course [12]. Alterations in hind limb weight bearing (WB) measured by an incapacitance test are widely used as a nociceptive behavioral outcome in the MIA model as the rat will carry less weight on a painful limb.…”

Prevalence of Neuropathic Pain in Rheumatic Disorders: Association With Disease Activity, Functional Status and Quality of Life

“…Also, previous studies indicated both nociceptive and neuropathic pain in rat models which had surgically and mono-iodoacetate-induced OA. 24,25 There are possible mechanisms that may explain neuropathic pain in OA. According to McDougall et al, 26 subclinical damage to peripheral nerves may be associated with neuropathic pain in knee OA.…”