Functional activity mapping of the rat spinal cord during formalin-induced noxious stimulation.

The functional activity pattern in the cervical enlargement of the spinal cord (as expressed by changes in local glucose utilization) was investigated by the semi-quantitative [14C]2-deoxyglucose technique 2 min ("early" group) or 60 min ("late" group) after injection of a small amount of dilute formalin (0.06-0.08 ml, 5%) in a forepaw of unanesthetized, freely-moving rats. Control animals were either injected with an equivalent volume of saline or simply handled. In both formalin groups a tonic flexion of the injected limb was present during the experiments, while supraspinal-integrated behavior (such as licking the affected paw) was sharply reduced in the late group. A bilateral increase of metabolic activity indexes, more pronounced on the ipsilateral side, was found in the "early" formalin-injected animals. The highest increase over control values was found in the medial part of the superficial (laminae I-II) region of the ipsilateral dorsal horn. However, the [14C]2-deoxyglucose uptake was found to be elevated over the whole extent of the dorsal horns, as well as in the gray matter surrounding the central canal, anterior horns and ipsilateral dorsolateral funiculus. In a parallel group of experiments performed in pentobarbital-anesthetized rats metabolic increases in the early period after formalin injection were less pronounced; they were only found in the ipsilateral side of the cord. In the "late" formalin group the overall metabolic changes were less conspicuous. They were mainly observed in the side ipsilateral to the injection, the highest increase being found in the deep portion (laminae V-VI) of the dorsal horn. Therefore, the spatial distribution of functional activation elicited during prolonged noxious stimulation in the spinal cord gray matter of unanesthetized rats varies according to time and changes in animal behavior.

Functional activity mapping of the rat brainstem during formalin-induced noxious stimulation.

Functional activity changes in 35 selected structures of the rat brainstem elicited by subcutaneous formalin injection in a forepaw were investigated by the [14C]2-deoxyglucose method in unanesthetized, freely moving animals. Experiments were initiated 2 min ("early" group) or 60 min ("late" group) after the injection. Treatment induced a significant increase of [14C]2-deoxyglucose uptake relative to controls in 17 structures of the "early" group, including portions of the bulbar, pontine and mesencephalic reticular formation, nucleus raphe magnus, median and dorsal raphe nuclei, the ventrolateral and dorsal subdivisions of the periaqueductal gray matter, deep layers of the superior colliculus and the anterior pretectal nucleus. Most changes were bilateral, with the exception of the increases observed in the nucleus reticularis paragigantocellularis and the lateral parabrachial area, which were contralateral, and the one in the mesencephalic reticular formation, which was ipsilateral to the injected paw. In pentobarbital-anesthetized rats a significant difference in metabolic activity values between formalin- and saline-injected animals was only detected at the medullary level. In the "late" unanesthetized formalin group functional activity levels were higher than controls in four structures, including the lateral reticular and paragigantocellular nuclei, contralaterally, and nucleus cuneiformis and ventrolateral periaqueductal gray matter, bilaterally. No between-groups difference was observed in visual or auditory structures. These results provide evidence for activation of several brainstem regions, which are conceivably involved in different sensory, motivational or motor circuits, during the initial phase of formalin-evoked noxious stimulation in unanesthetized animals. Functional changes blunted over time as did pain-related behavior integrated at the supraspinal level, but they persisted in some brainstem regions for which involvement in endogenous antinociceptive systems have been suggested. The mechanisms underlying these time-related changes need to be clarified.