This is the first neural imaging study to use regional cerebral blood flow (rCBF) in an animal model to identify the patterns of forebrain nociceptive processing that occur during the early and late phase of the formalin test. We measured normalized rCBF increases by an autoradiographic method using the radiotracer [ 99m Tc]exametazime. Noxious formalin consistently produced detectable, welllocalized and typically bilateral increases in rCBF within multiple forebrain structures, as well as the interpeduncular nucleus (Activation Index, AI = 66) and the midbrain periaqueductal gray (AI = 20).Structures showing pain-induced changes in rCBF included several forebrain regions considered part of the limbic system. The hindlimb region of somatosensory cortex was significantly activated (AI = 31), and blood flow increases in VPL (AI = 8.7) and the medial thalamus (AI = 9.0) exhibited a tendency to be greater in the late phase as compared to the early phase of the formalin test. The spatial pattern and intensity of activation varied as a function of the time following the noxious formalin stimulus. The results highlight the important role of the limbic forebrain in the neural mechanisms of prolonged persistent pain and provide evidence for a forebrain network for pain.

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The latency of the heat-activated rat tail-flick (TF) reflex is dependent upon 4 variables, none of which has previously been determined: activation of cutaneous nociceptors (TN); afferent conduction to the dorsal horn (TA); conduction within the central nervous system (CNS) (central delay); and conduction from the ventral horn (VH) to, and activation of, tail muscles (TE). Using a CO2 infrared laser (10 W, 45 msec) to produce synchronous activation of tail-skin nociceptors, TF latency (EMG response) was measured in 10 awake rats. Based on shifts in response latency from points of stimulation near the tip and base of the tail, conduction velocity in the afferent limb of the reflex was estimated to be 0.76 +/- 0.11 m/sec. This indicates that the response is mediated by C fibers. The rats were then anesthetized with pentobarbital and multiple-unit activity and evoked potentials (EPs) were recorded from the superficial dorsal horn at spinal segments S3-CO1 during laser or high-intensity electrical (10 mA, 1 msec) stimulation of the tail. Unit activity and EPs elicited by both stimuli consisted of two distinct components, corresponding to activation of A and C fibers. The difference in latency between laser and electrical evoked activity indicated that 60.00 +/- 7.33 msec was required for activation of nociceptors by the laser. Electrical stimulation of the VH at S3-CO1 in 3 rats produced a TF (EMG) response in 4 msec. Central delay, calculated as total TF time minus (TN+TA+TE), was 82.3 +/- 13.08 msec. This represents the time frame during which modulation of the reflex by an intrinsic, pain-activated, supraspinal system could occur.

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