Background & Aims
Approximately 30% of stroke survivors develop post stroke pain (PSP) which significantly impacts on their quality of life. The pathophysiology of PSP is not fully understood. Treatment is extremely challenging, response to therapy is variable and many of the medications used have undesirable side-effects. There is a clear unmet need for new therapies for PSP.
Preclinical models used to mimic focal ischemia include transient or permanent occlusion of the middle cerebral artery (t- or p-MCAO). Although these models have been used extensively to study neuroprotection, post stroke pain has received little or no attention. We have recently used these models to study PSP in mice.
In this study, we investigated the development of PSP in mice undergoing t- or p-MCAO and investigated the effects of carnosine (a neuroprotective pleotropic endogenous dipeptide, known to reduce the ischemic damage and to improve the neurological functional outcome) on post stroke pain.
Methods
Experiments were carried out using C57 mice (20-25g at time of surgery).
Permanent MCAO: Under anaesthesia a craniotomy was performed on top of the left MCA, using electrocoagulator forceps a permanent occlusion of the MCA was performed proximally and distally to the bifurcation.
Transient MCAO: Under anaesthesia an intraluminar monofilament was inserted into the left common carotid artery, advanced distal to the bifurcation into the internal CA until it reaches the distal end of the MCA. The filament was kept in place for 60 min, after which was removed and reperfusion allowed.
Behaviour assessment: Testing of nociceptive sensitivity was performed on the plantar surface of the hindpaw using calibrated von Frey filaments and radiant heat stimuli.
Western Blot and Immunofluorescence: at day 28 following ischemia spinal cord were isolated and processed for evaluation of protein expression.
Results
Mice undergone p – or t-MCAO developed both thermal hypersensitivity and mechanical allodynia only in the limbs contralateral to the focal ischemia. Hypersensitivity started from day 7 post onset of ischemia and lasted over 28 days. The hypersensitivity was attenuated by administration of carnosine at either the onset or at 24hrs after ischemia. Critically, our data also suggest that expression of CGRP and MMP-9 was enhanced in the lumbar spinal cord of mice with p-MCAO.
Conclusions
The results of this study showed that mice with p-or t-MCAO developed post stroke pain, which was attenuated by carnosine, offering new insights into the treatment of post stroke pain. However, further investigations are required to advance our understanding of the mechanisms behind post stroke pain and how carnosine affect these mechanisms
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