Research reportEffect of post-injury NMDA antagonist treatment on long-term Fos expression and hyperalgesia in a model of chronic neuropathic pain
Introduction
In the accompanying paper [23], we report that expression of the protein product of the immediate early gene c-fos may be initiated by NMDA-dependent mechanisms in the spinal cord of rats that had undergone chronic constrictive injury (CCI) of the sciatic nerve according to the model of Bennett and Xie [3]. Pre-injury treatment with the NMDA antagonist MK-801 could suppress both Fos expression and mechanical hyperalgesia at 28 days after injury In contrast, Fos expression following associated with surgical trauma and inflammation following sham operation, while quantitatively similar to that of CCI, was insensitive to pre-injury treatment with MK-801 indicating that this pattern of expression may be initiated by non-NMDA receptor mediated processes within the spinal cord.
Sciatic nerve CCI is a model of human neuropathic pain where `injury discharge' leads to pathological release of primary afferent transmitters including glutamate in the spinal cord dorsal horn [18]. Consequent NMDA receptor-activation initiates a cascade of events within the spinal cord that manifest as guarding of the affected limb, allodynia and mechanical hyperalgesia although the role of NMDA receptor-activation in the maintenance of long-term hyperalgesia in this model is less well defined. Fos expression can identify those populations of spinal interneurons and projection neurones that are activated within the spinal cord following injury 10, 20and the aims of this study were to determine the effect of MK-801 treatment administered 28 days after injury to animals with established hyperalgesia on: (i) long-term Fos expression in the spinal cord and (ii) to evaluate the relationship between Fos expression and hyperalgesia in these animals.
Section snippets
Treatment of animals
All procedures were performed on Glaxo-bred random hooded rats (male 150–200 g) treated as previously described [23]and in accordance with the IASP guidelines on the use of animals for investigation of experimental pain [39]. Mononeuropathy or sham operation was performed according to Bennett and Xie [3]and as previously described [23]and animals were allowed to recover for periods of up to 55 days.
On days 28–34 following operation, animals received daily subcutaneous injections of either
Results
A total of 40 operated and two naı̈ve control animals were used in this study. The numbers and treatment of animals examined at each time point were as follows: (time point; no. of sham animals, no. of CCI animals) day 14; 3, 5: day 35 saline treated; 3, 4: day 35 MK-801 treated; 4, 4: day 55 saline treated; 3, 5: day 55 MK-801 treated; 3, 6.
Discussion
In this study, sciatic nerve ligation resulted in the development of long-lasting mechanical hyperalgesia that could be temporarily suppressed by systemic administration of the NMDA open channel blocker MK-801 28–34 days after nerve ligation. The elimination half life of MK-801 after systemic administration in the rat has been reported to be 1.65 h [8], and it has been previously reported that an equivalent dosage regimen to that used in this study produces motor and behavioural deficits
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Physiology and Pathophysiology of Chronic Pain
2009, NeuromodulationExpression of c-Fos in the parabrachial nucleus following peripheral nerve injury in rats
2008, European Journal of PainCitation Excerpt :In experimental pain research, immunohistochemical detection of c-Fos protein is widely used for identification of post-synaptic neurons activated by nociceptive stimuli (Hunt et al., 1987; Bullitt, 1989; Menetrey et al., 1989; Lima and Avelino, 1994; Harris, 1998; Lima, 1998). In the chronic constriction injury (CCI) model (Bennett and Xie, 1988) of neuropathic pain, the expression of c-Fos protein has been observed in spinal dorsal horn neurons as well as in deep dorsal horn layers at different post-injury periods (Kajander et al., 1996; Catheline et al., 1999; Hudspith et al., 1999; Yamazaki et al., 2001; Jergova and Cizkova, 2005). However, there is a lack of information on the pattern of c-Fos expression and the localization of nociceptive-responding neurons among the brain stem neurons following CCI.
Fos, nociception and the dorsal horn
2005, Progress in NeurobiologyLong-term changes of c-Fos expression in the rat spinal cord following chronic constriction injury
2005, European Journal of Pain