Improgan is a compound developed from histamine antagonists which shows the pre-clinical profile of a highly effective, non-opioid analgesic when administered into the rodent CNS. Pharmacological studies suggest that improgan activates descending pain-relieving circuits, but the brain and spinal sites of action of this drug have not been previously studied. Presently, the effects of intracerebral and intrathecal microinjections of improgan were evaluated on thermal nociceptive responses in rats. Improgan produced large, dose- and time-related reductions in nociceptive responses following administration into the ventrolateral periaqueductal gray (PAG), the dorsal PAG, and the rostral ventromedial medulla (RVM). The drug had no measurable effects after injections into the caudate nucleus, basolateral amygdala, hippocampus, ventromedial hypothalamus, superior colliculi, ventrolateral medulla, or the spinal subarachnoid space. Inactivation of the RVM by muscimol microinjections completely attenuated antincociceptive responses produced by intraventricular improgan. These findings, taken with earlier results, show that, like opioids and cannabinoids, improgan acts in the PAG and RVM to activate descending analgesic systems. Unlike these other analgesics, improgan does not act in the spinal cord or in CNS areas outside of the brain stem. © 2004 Elsevier B.V. All rights reserved.