Pain-like behaviour and spinal changes in the monosodium iodoacetate model of osteoarthritis in C57Bl/6 mice

TY - JOUR

T1 - Pain-like behaviour and spinal changes in the monosodium iodoacetate model of osteoarthritis in C57Bl/6 mice

AU - Ogbonna, A. C.

AU - Clark, A. K.

AU - Gentry, C.

AU - Hobbs, C.

AU - Malcangio, M.

PY - 2013/4

Y1 - 2013/4

N2 - Background Osteoarthritis (OA) is a highly prevalent, age-related pain condition that poses a significant clinical problem. Here, in the monosodium iodoacetate (MIA) model of OA, we have characterized pain behaviours and associated changes at the first pain synapse in the dorsal horn of the spinal cord. Methods Mice received intra-articular injections of 0.5, 0.75 and 1mg MIA and mechanical paw withdrawal threshold was monitored for up to 4 weeks. An intrathecal injection of peptide antagonist calcitonin gene-related peptide (CGRP8-37) was given 3 weeks post MIA and paw withdrawal thresholds were measured after 1 and 3 h. Immunohistochemical analysis of the lumbar dorsal horn was carried out and activity-evoked CGRP release was measured from isolated lumbar dorsal horn slices with dorsal roots attached. Results By 2 weeks after intra-articular MIA 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 1mg MIA. However, both dorsal horn neuron activation and microglial response (Fos and Iba-1 immunostaining) but not reactive astrocytes (glial fibrillary acidic protein) were observed. Evoked CGRP release was greater from dorsal horn slices of MIA-treated mice compared with control. Furthermore, intrathecal administration of peptide antagonist CGRP8-37 acutely attenuated established MIA-induced mechanical hypersensitivity. Conclusions Intra-articular MIA is associated with referred mechanical hypersensitivity and increased release of CGRP from primary afferent fibres in the dorsal horn where second-order neuron activation is associated with a microglial response. Antagonism of CGRP receptor activation provides a therapeutic avenue for the treatment of pain in OA.

AB - Background Osteoarthritis (OA) is a highly prevalent, age-related pain condition that poses a significant clinical problem. Here, in the monosodium iodoacetate (MIA) model of OA, we have characterized pain behaviours and associated changes at the first pain synapse in the dorsal horn of the spinal cord. Methods Mice received intra-articular injections of 0.5, 0.75 and 1mg MIA and mechanical paw withdrawal threshold was monitored for up to 4 weeks. An intrathecal injection of peptide antagonist calcitonin gene-related peptide (CGRP8-37) was given 3 weeks post MIA and paw withdrawal thresholds were measured after 1 and 3 h. Immunohistochemical analysis of the lumbar dorsal horn was carried out and activity-evoked CGRP release was measured from isolated lumbar dorsal horn slices with dorsal roots attached. Results By 2 weeks after intra-articular MIA 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 1mg MIA. However, both dorsal horn neuron activation and microglial response (Fos and Iba-1 immunostaining) but not reactive astrocytes (glial fibrillary acidic protein) were observed. Evoked CGRP release was greater from dorsal horn slices of MIA-treated mice compared with control. Furthermore, intrathecal administration of peptide antagonist CGRP8-37 acutely attenuated established MIA-induced mechanical hypersensitivity. Conclusions Intra-articular MIA is associated with referred mechanical hypersensitivity and increased release of CGRP from primary afferent fibres in the dorsal horn where second-order neuron activation is associated with a microglial response. Antagonism of CGRP receptor activation provides a therapeutic avenue for the treatment of pain in OA.

KW - PRIMARY SENSORY NEURONS

KW - NEUROPATHIC PAIN

KW - RAT MODEL

KW - NERVE INJURY

KW - SUBSTANCE-P

KW - JOINT PAIN

KW - KNEE-JOINT

KW - PHARMACOLOGICAL CHARACTERIZATION

KW - RECEPTOR ANTAGONISTS

KW - KNOCKOUT MICE

U2 - 10.1002/j.1532-2149.2012.00223.x

DO - 10.1002/j.1532-2149.2012.00223.x

M3 - Article

SN - 1090-3801

VL - 17

SP - 514

EP - 526

JO - EUROPEAN JOURNAL OF PAIN

JF - EUROPEAN JOURNAL OF PAIN

IS - 4

M1 - N/A

ER -