Abstract
Sigma-1 receptor (σ1R) knockout (KO) CD1 mice, generated by homologous recombination, and separate pharmacological studies in wild type (WT) mice were done to investigate the role of this receptor in the development of pain-related behaviours (thermal hyperalgesia and mechanical allodynia) in mice after spinal cord contusion injury (SCI) – a model of central neuropathic pain. The modulatory effect of σ1R KO on extracellular mediators and signalling pathways in the spinal cord was also investigated. In particular, changes in the expression of inflammatory cytokines (tumour necrosis factor TNF-α, interleukin IL-1β) and both the expression and activation (phosphorylation) of the N-methyl-D-aspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analysed. Compared with WT mice, both mechanical and thermal hypersensitivity were attenuated in σ1R KO mice following SCI. Accordingly, treatment of WT mice with the σ1R antagonist MR309 (previously developed as E-52862; S1RA) after SCI exerted antinociceptive effects (i.e. reduced mechanical allodynia and thermal hyperalgesia). Attenuated nociceptive responses in σ1R KO were accompanied by reduced expression of TNF- α and IL-1β as well as decreased activation/phosphorylation of NR2B-NMDA receptors and ERK1/2. These findings suggest that σ1R may modulate central neuropathic pain and point to regulation of sensitization-related phenomena as a possible mechanism.
Highlights
Spinal cord injury (SCI) may trigger central neuropathic pain, which is defined as the pain caused by a lesion or disease of the central somatosensory nervous system[1]
Our findings indicate that mechanical allodynia and thermal hyperalgesia found after spinal cord contusion injury (SCI) in wild type (WT) mice are significantly attenuated in mice lacking σ1R, up to four weeks after injury
Mechanical allodynia was reduced an average of 54% and thermal hyperalgesia was reduced an average of 51% in σ1R KO versus WT mice
Summary
Spinal cord injury (SCI) may trigger central neuropathic pain, which is defined as the pain caused by a lesion or disease of the central somatosensory nervous system[1]. The present study comprised two independent sets of experiments to investigate the role of this chaperone protein in the development of central neuropathic pain-related behaviours after mild spinal cord contusion injury in mice. Σ1R KO animals have been used to investigate the role of σ1R in animal models where pain was primarily induced at the periphery, such as paw capsaicin and formalin injection[24,25], inflammatory pain models[26,27], and peripheral neuropathic models, including sciatic constriction injury[12] and paclitaxel-induced neuropathy[28] In all these models, pain-related behaviours (e.g., formalin-induced paw licking/biting, capsaicin-induced mechanical allodynia or nerve injury-induced mechanical allodynia) were absent or attenuated in σ1R KO mice compared to WT mice. In the present study WT and σ1R KO mice were subjected to spinal cord contusion[29] and their responses to mechanical and thermal stimulation recorded up to 4 weeks after injury
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