Involvement of glutamatergic neurotransmission and protein kinase C in spinal plasticity and the development of chronic pain.
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J Schadrack
Publications and source records attributed to J Schadrack.
Anticonvulsants suppress c-Fos protein expression in spinal cord neurons following noxious thermal stimulation.
The expression of the nuclear immediate-early gene-encoded protein c-Fos in spinal cord dorsal horn neurons of the rat following noxious thermal stimulation was compared in carbamazepine-, valproate- and phenytoine-treated animals. Single intraperitoneal injection of carbamazepine (50 mg/kg), valproate (300 mg/kg) or intravenous injection of phenytoine (20 mg/kg) before noxious stimulation reduced the number of c-Fos immunoreactive neurons to 65-80% of control levels in superficial laminae and to 30-60% in deep laminae of the dorsal horn. Pretreatment with carbamazepine or valproate for 4 or 8 days combined with an injection immediately before noxious stimulation further significantly decreased the number of c-Fos neurons in the deep dorsal horn only in animals treated with valproate. The observation that activity-dependent gene expression in the spinal cord is effectively modulated by anticonvulsants discloses a novel therapeutic potential of these compounds. Presumably via an acute suppression of high-frequency repetitive firing and/or altered synaptic transmission of intraspinal or descending neurotransmitter systems these drugs gain access to neuroplastic mechanisms which might be relevant for the restoration of physiological levels of neuronal excitability in the central nervous system.
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Application of morphine prior to noxious stimulation differentially modulates expression of Fos, Jun and Krox-24 proteins in rat spinal cord neurons.
The expression of Fos, Jun and Krox-24 proteins was investigated in spinal cord neurons of the rat 2, 4 and 8 h following noxious thermal stimulation of one hind-paw and pre-treatment with morphine. The number of neurons expressing c-Fos, c-Jun, Jun B and Krox-24 were maximal after 2 h and thereafter declined. The number of Fos B and Jun D immunoreactive neurons increased constantly for up to 8 h with Jun D showing expression above baseline only after 4 h following stimulation. Intravenous application of morphine (5 and 10 mg/kg) 20 min before noxious heat stimulation decreased the expression of all six proteins at any time-point with a predilective effect on neurons of deeper laminae of the dorsal horn. The suppressive effects of morphine were more pronounced with the higher dose of morphine and completely reversed by intravenous naloxone (1 and 10 mg/kg). The temporospatial patterns of expression following morphine were similar to those seen without morphine, but in a much smaller number of neurons and with a shorter time-course. However, despite the high dose of morphine and continuous halothane anaesthesia during the whole experimental procedures, a considerable number of neurons expressing the various genes remained in all laminae of the spinal cord. At 2 h following noxious heat stimulation morphine had decreased the number of labelled neurons for c-Fos, Fos B, Krox-24, c-Jun and Jun B to 30-60% of control levels in laminae I-II and to 10-30% in laminae III-VII,X of the spinal cord. At 4 h the level of reduction had further increased while Jun D was only moderately reduced to 75% in all laminae of the spinal cord. Eight hours following noxious heat plus morphine application we did not detect noxious evoked immunoreactivity for c-Fos, Krox-24, c-Jun and Jun B, while there was residual labelling for Fos B in the superficial dorsal horn and for Jun D in laminae I-VII and X of the spinal cord. The different temporospatial pattern of immediate early gene expression in neurons of the spinal cord dorsal horn following noxious stimulation suggest that variable transcription complexes may interact with DNA regulatory sequences and could thus activate alternative secondary response genes, even under protection of a high dosage of morphine applied before noxious stimulation.
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