Traumatic nociceptive pain activates the hypothalamus and the periaqueductal gray: a positron emission tomography study

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Abstract
The study was conducted to investigate which areas of the brain respond to a painful encounter of minor dermal injury (a model of clinical pain) elicited by intracutaneous injection of a minute amount of ethanol. Four healthy volunteers (27-46 years) were subjected to positron emission tomographic (PET) investigation of regional cerebral blood flow (rCBF), using [15O]butanol as tracer. The ethanol (20 microliters, 70%) and saline (20 microliters, 0.9%) were injected intracutaneously 3 times in a single-blinded, semi-randomised manner for the pain experiment. All the injections were performed, adjacent to each other, at the lateral aspect of the right upper arm. Subjective sensory intensity of pain, unpleasantness and anxiety were rated with separate 100-mm visual analogue scales together with the Spielberger's State Anxiety Inventory (Spielberger et al. 1970) and heart rate. Paired-subtraction (pixel-by-pixel) between ethanol and saline was performed. Traumatic pain significantly caused higher ratings of intensity and affect scales, i.e., pain intensity, unpleasantness and increased sympathetic activity (evidenced by tachycardia). In contrast the anxiety rating remained unchanged. Acute traumatic nociceptive pain prominently activated the hypothalamus and periaqueductal gray (PAG). In addition, activations of the prefrontal cortex (PFC), insular, anterior cingulate cortex (ACC), posterior parietal cortex (PPC), primary motor/somatosensory areas (MI/SI: face, upper arm), supplementary motor area (SMA), and cerebellum were also demonstrated. The central processing of the pain-relevant/anticipatory arousal also engaged the PAG. This study demonstrates the involvement of the human cerebral cortex in perception, arousal, cognitive evaluative processes, and, hence, affective reactions (somatic/ autonomic outflow) associated with pain. The pain stimulus of traumatic character may, by its very nature, evoke the central processing to involve both the hypothalamus and the PAG.