The experiments described in the present study approached nerve injury from both a biochemical and anatomical perspective by monitoring changes in expression of preprotachykinin (PPT) mRNA encoding the prototypic tachykinin substance P and related peptide species in neurons of the rat dorsal root ganglia (DRG) following unilateral chronic constriction injury of the sciatic nerve. In situ hybridization histochemistry (ISHH) analyses in conjunction with computer-assisted image processing were employed to quantify levels of PPT mRNA distributed in DRG neurons. Injury-induced changes in PPT mRNA expression by affected DRG neurons included: (1) at early postoperative times, generally increased levels of PPT mRNA associated with small and intermediate-size B cells exhibiting normal morphology, (2) at late postoperative times, markedly decreased levels of PPT mRNA associated with degenerating B cells, and (3) induction of PPT gene expression by large A cells which is highly correlated with degenerative morphological changes. The significant aspects of these changes are discussed with special emphasis on the contribution of altered transmitter expression by DRG neurons to the pathophysiology of causalgia. In particular, the induction of PPT gene expression by many of the large neurons undergoing degenerative changes may represent an important biochemical parameter which is associated with the development and persistence of experimental allodynia.
Cardiovascular depression occurring when diazepam is combined with fentanyl has been investigated using the benzodiazepine antagonist RO15-1788 in the dog. After the initial administration of fentanyl (40 mcg/kg), the mean arterial pressure (MAP) decreased to 89% of its control value. Following the administration of diazepam (1.2 mg/kg), the MAP and the total peripheral resistance (TPR) decreased significantly, to 75% and 83% of their control values respectively. After the administration of RO15-1788 (0.4 mg/kg), the MAP increased significantly to 90% and the TPR to 102% of their control values and, lastly, the administration of naloxone (40 mcg/kg) increased the MAP to 108% of its control value. No relationship was found between the changes in the catecholamines and the changes in the MAP after the administration of fentanyl, diazepam, and RO15-1788. The mechanism of circulatory depression when diazepam was used with fentanyl is interpreted as being a peripheral vasodilatory effect of diazepam acting by way of the benzodiazepine receptors since RO15-1788 was found to antagonize this effect.
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