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Substantial data are accumulating that implicate the lateral hypothalamus (LH) as part of the descending pain modulatory system. The LH modifies nociception in the spinal cord dorsal horn partly through connections with the periaqueductal gray (PAG), an area known to play a central role in brainstem modulation of nociception. Early work demonstrated a putative substance P connection between the LH and the PAG, but the connection is not fully defined. To determine whether LH-induced antinociception mediated by the PAG is neurokinin1 (NK1) receptor-dependent, we conducted behavioral experiments in which the cholinergic agonist carbachol (125 nmol) was microinjected into the LH of lightly anesthetized female Sprague-Dawley rats (250–350 g) and antinociception was obtained on the tail flick or foot withdrawal tests. Cobalt chloride (100 nM), which reversibly blocks synaptic activation, blocked LH-induced antinociception. In another set of experiments, the specific NK1 receptor antagonist L-703-606 (5 μg) was microinjected in the PAG following LH stimulation with carbachol abolished LH-induced antinociception as well. Microinjection of cobalt chloride or L-703,606 in the absence of LH stimulation had no effect. These behavioral experiments coupled with earlier work provide converging evidence to support the hypothesis that antinociception produced by activating neurons in the LH is mediated in part by the subsequent activation of neurons in the PAG by NK1 receptors.

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