Modulation of neuronal activity in CNS pain pathways following propofol administration in rats: Fos and EEG analysis

Abstract

We studied Fos expression in the central nociceptive pathways at different sedative levels in order to clarify the central mechanism of propofol's nociceptive action. Sprague-Dawley rats received propofol (PRO) or pentobarbital (PEN) and were divided into two groups with different doses of drug administration (light and deep sedative levels) based on the electroencephalogram analysis. Rats at each sedative level received heat stimulation to their face and Fos immunohistochemistry was performed at various brain sites. We also infused lidocaine into the jugular vein to test whether PRO directly activated nociceptors distributed in the vein. Fos expression in two major ascending pain pathways (lateral and medial systems) and descending modulatory system were precisely analyzed following intravenous (i.v.) administration of PRO or PEN. Many Fos protein-like immunoreactive (Fos protein-LI) cells were expressed in the trigeminal spinal nucleus caudalis (Vc), parabrachial nucleus, parafascicular nucleus, a wide area of the primary somatosensory cortex, anterior cingulate cortex, amygdala, periaqueductal gray, solitary tract nucleus, and lateral hypothalamus following heating of the face during PRO or PEN infusion. The number of Fos protein-LI cells was significantly greater in many Central nervous system regions during PRO infusion compared with PEN. Fos expression was significantly greater in the Vc and Periaqueductal gray following greater amount of PRO infusions compared, whereas they were significantly smaller in the Vc in the rats with PEN infusion. The Fos expression was significantly depressed following i.v. infusion of lidocaine before PRO administration. The present findings suggest that PRO is involved in the enhancement of Vc activity through direct activation of the primary afferent fibers innervating veins, resulting in pain induction during infusion.

Increased Phosphorylation of Extracellular Signal-Regulated Kinase in Trigeminal Nociceptive Neurons Following Propofol Administration in Rats

“…It has been shown that PRO has a depressive action on neuronal activity in the whole brain areas, reflected by a decrease in EEG activity 26. We observed a similar EEG depression in rats that is observed in humans during PRO infusion.…”

“…1A and B. Studies show that the depth of hypnosis can be evaluated in animals by i-EEG analysis in which the EEG amplitude was measured and the duration of amplitude depression was calculated 4,10,15,26,31,33,46,47. Thus, we introduced the i-EEG analysis to measure the depth of hypnosis during intravenous administration of PRO or PEN.…”

“…The EEG activity was rectified and the time points with peak EEG amplitudes were detected using spike 2 software and the i-EEG was calculated according to the previous study by Kubota et al26 When more than 40 % reduction of the EEG amplitude was obtained during drug infusion, the hypnotic level was defined DEEP (PRO: 2.52 ± 0.21 mg/kg/min, PEN: 2.25 ± 0.15 mg/kg/min, approximately 15–20 min in each drug) as illustrated in Fig. 1C, D and E.…”

“…We have shown recently that propofol modulates neuronal activation in CNS pain pathways, as indicated by Fos protein expression, after noxious thermal stimulation of the face 26. In the present study, we have used pERK as a marker to systematically analyze the effect of propofol on neuronal activation in the spinal trigeminal complex and upper cervical spinal cord in response to capsaicin, a commonly used chemical irritant that produces central sensitization and hyperalgesia 52.…”

Propofol induces ERK-dependant expression of c-Fos and Egr-1 in neuronal cells

“…However, the same studies showed that high concentrations of propofol did not affect the expression of c-Fos, JunB, or Egr-1 in culture [10,11]. In contrast, Hamaya et al [12] reported that propofol increases the expression of c-Fos and Jun B in the rat brain; whereas Kubota and coworkers [13] showed that propofol regulates the expression of c-Fos in brain slices. Therefore, the interaction between propofol and these immediate early transcription factors is still under debate.…”