In essence, the clinical goal of general anesthesia is to produce a state of unresponsiveness and amnesia. These endpoints are commonly achieved with drugs like isoflurane, but the sites and mechanisms by which these specific endpoints are achieved remain unknown. Blocking the somatic motor response to painful stimuli is widely used as an indicator of anesthetic adequacy, and the concentration of anesthetic agent (minimum alveolar concentration [MAC]) required to achieve this unresponsiveness is the benchmark of anesthetic potency. Recent work has demonstrated that precollicular decerebration does not alter MAC in rats, suggesting that the forebrain is not a major site of action of isoflurane in blocking motor responses. The brain stem contains systems that modulate pain processing in the spinal cord. The current study was undertaken to assess the relative roles of the brain stem and spinal cord as sites of anesthetic action in blocking somatic responsiveness. In seven rats, anesthesia was induced and maintained with isoflurane in oxygen. MAC was determined by observing the response to tail clamp and fore- and hind limb toe pinch at three times: after intubation, after cervical laminectomy, and after staged hypothermic spinal cord transection. MAC determined by tail clamp did not change during the protocol (1.28 +/- 0.08% [mean +/- standard deviation] baseline vs. 1.25 +/- 0.18% postlaminectomy vs. 1.03 +/- 0.40% posttransection). In one animal, the MAC value decreased from a prelesion value of 1.2% to 0.25%, accounting for most of the variance in the postlesion mean; the MAC value as determined by withdrawal to rear paw pinch was unchanged from its prelesion value in this animal. The MAC values as determined by toe pinch in all animals remained unchanged after spinal transection of the lesion both rostrally and caudally. Somatic motor responsiveness and its sensitivity to isoflurane appeared to be unaltered despite acute loss of descending cortical and bulbar controls. This observation suggests that the site of anesthetic inhibition of motor response may be in the spinal cord.