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.

HES-B and HES-C are equally retained in the blood vessels. Middle-sized HES-B with low DS and middle substitution pattern stayed in the blood vessels as long as the large-sized HES. HES solutions of varying characters should be examined to optimize HES infusion.

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Propofol (PRO) is frequently used as the reliable sedative agent in clinic situation because it is safe and easy to control the depth of sedative level. PRO, however, has weak analgesic action even causing acute pain sensation during intravenous infusion. For the clinical use of sedatives, the invasive action such as pain should be relieved. It is very important to know underlying mechanisms of the weak analgesic action of propofol in order to improve clinical use of PRO. We studied the phosphorylated Extracellular Signal-regulated Kinase (pERK) expression in the trigeminal spinal nucleus and upper cervical nociceptive neurons to clarify the central mechanism of the enhancement of trigeminal transmission. We observed that a large number of pERK-LI cells were expressed in Vi/Vc zone, middle Vc and Vc-C2 zone immediately after the large amount of propofol injection. The number of pERK-LI cells was increased following increase in the amount of PRO administration. We also observed that the expression of pERK-LI cells was depressed after the lidocaine injection before PRO injection. The present findings suggest that PRO has a strong ability to enhance nociceptive neuronal activity in the trigeminal region through the primary afferent nociceptors innervated in the cervical vein, resulting in the central sensitization of the trigeminal nociceptive pathways during infusion.

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