Pain‐like behaviour and spinal changes in the monosodium iodoacetate model of osteoarthritis in <scp>C57Bl</scp>/6 mice

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Osteoarthritis (<jats:styled-content style="fixed-case">OA</jats:styled-content>) is a highly prevalent, age‐related pain condition that poses a significant clinical problem. Here, in the monosodium iodoacetate (<jats:styled-content style="fixed-case">MIA</jats:styled-content>) model of <jats:styled-content style="fixed-case">OA</jats:styled-content>, we have characterized pain behaviours and associated changes at the first pain synapse in the dorsal horn of the spinal cord.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Mice received intra‐articular injections of 0.5, 0.75 and 1 mg <jats:styled-content style="fixed-case">MIA</jats:styled-content> and mechanical paw withdrawal threshold was monitored for up to 4 weeks. An intrathecal injection of peptide antagonist calcitonin gene‐related peptide (<jats:styled-content style="fixed-case">CGRP</jats:styled-content><jats:sub>8‐37</jats:sub>) was given 3 weeks post <jats:styled-content style="fixed-case">MIA</jats:styled-content> and paw withdrawal thresholds were measured after 1 and 3 h. Immunohistochemical analysis of the lumbar dorsal horn was carried out and activity‐evoked <jats:styled-content style="fixed-case">CGRP</jats:styled-content> release was measured from isolated lumbar dorsal horn slices – with dorsal roots attached.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>By 2 weeks after intra‐articular <jats:styled-content style="fixed-case">MIA</jats:styled-content> injection, mechanical hypersensitivity was established in the ipsilateral hindpaw. There was no evidence of sensory neuron damage in lumbar dorsal root ganglia 7 days after 1 mg <jats:styled-content style="fixed-case">MIA</jats:styled-content>. However, both dorsal horn neuron activation and microglial response (<jats:styled-content style="fixed-case">F</jats:styled-content>os and <jats:styled-content style="fixed-case">I</jats:styled-content>ba‐1 immunostaining) but not reactive astrocytes (glial fibrillary acidic protein) were observed. Evoked <jats:styled-content style="fixed-case">CGRP</jats:styled-content> release was greater from dorsal horn slices of <jats:styled-content style="fixed-case">MIA</jats:styled-content>‐treated mice compared with control. Furthermore, intrathecal administration of peptide antagonist <jats:styled-content style="fixed-case">CGRP</jats:styled-content><jats:sub>8‐37</jats:sub> acutely attenuated established <jats:styled-content style="fixed-case">MIA</jats:styled-content>‐induced mechanical hypersensitivity.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Intra‐articular <jats:styled-content style="fixed-case">MIA</jats:styled-content> is associated with referred mechanical hypersensitivity and increased release of <jats:styled-content style="fixed-case">CGRP</jats:styled-content> from primary afferent fibres in the dorsal horn where second‐order neuron activation is associated with a microglial response. Antagonism of <jats:styled-content style="fixed-case">CGRP</jats:styled-content> receptor activation provides a therapeutic avenue for the treatment of pain in <jats:styled-content style="fixed-case">OA</jats:styled-content>.</jats:p></jats:sec>