Impaired Spinal Cord Plasticity Of Primary Sensory Neurons In Iodoacetate-induced Osteoarthritis Pain

[Objective]Osteoarthritis (OA) is a prevalent joint disease with chronic, debilitating pain that is often refractory to analgesia. The monosodium iodoacetate (MIA) knee OA model has been widely used for the evaluation of OA pain, but the pathogenesis of associated chronic pain are not fully understood and may involve mechanisms combining joint degeneration, neurogenic inflammation, and neuropathic injury. Therefore, this study aims at revealing the mechanisms of neuropathic pain of knee osteoarthritis by use of MIA knee OA model.[Methods]Majority of the primary sensory neurons in the dorsal root ganglion (DRG) are small-sized nociceptive neurons that engage distinct central circuits, sense damage, and mediate pain and temperature sensation. These neurons can be roughly divided into isolectin B4 (1B4) binding (non-peptidergic) and calcitonin gene-related peptide (CGRP) expressing (peptidergic) populations. As a neuroanatomical feature, they extend long processes to peripheral tissues and converge their central axons symmetrically into the distinct anatomy territories in the spinal dorsal horns where they end as presynaptic terminals, with CGRP central terminals in laminae I and outer II whereas IB4 central terminals in inner lamina II. In the present study, we provided immunohistochemical (IHC) evidence of a defective spinal cord (SC) plasticity of the primary sensory neurons in iodoacetate-induced knee osteoarthritis (OA). Experimental OA was induced in rats by knee injection of monosodium iodoacetate (MIA,2mg). Behavior tests include mechanical allodynia, mechanical hyperaglsia, cooling stimulation, heating stimulation and weight bearing asymmetry. Central plasticity of primary nociceptive neurons was evaluated by IHC labeling of the central terminal patterns of IB4 (nonpeptidergic) and CGRP (peptidergic) axons on lumbar (L) SC sections at 5-week after induction of knee OA. In parallel, the profiles of IB4-and CGRP-positive neurons in L3-L5 dorsal root ganglia (DRG) were determined.[Results]MIA rats exhibited constant neuropathic pain and asymmetric hindlimb weight bearings. Significant reduction of IB4 (35±4%, p＜0.001) and CGRP (15±3%, p<0.01) staining in the ipsilateral superficial lamina of SCs in MIA rats was evident compared to the contralateral sides, as well as staining from saline-injected control rats (n= 5 animals per group). However, on average, the percentage of neurons binding IB4 in the ipsilateral L5 DRGs of MIA rats was increased to 61 ±6% compared to 47±1% in L5 DRGs from control rats (n=5 animals for each group, p<0.01) whereas the percentage of IB4-positive neurons in the ipsilateral L3 and L4 DRGs was comparable between MIA and control rats. Average percentage of CGRP labeled neurons in L3-L5 from MIA rats was not altered. Additionally, decreased CaMKII and TrkA in the ipsilateral superficial laminae of SCs of MIA rat but not in DRGs were also observed.[Conclusion]Our preliminary results indicate that MIA-induced OA pain displayed a reduction of the central innervation of nociceptive sensory axons, which was not corresponding to the staining profiles of these markers in the neuronal somata in DRGs. These data suggest that the SC plasticity or central axonal transport process for the primary sensory neurons in MIA OA rats was impaired.