Spinal Sources of Noxious Visceral and Noxious Deep Somatic Afferent Drive Onto the Ventrolateral Periaqueductal Gray of the Rat COLIN I. CLEMENT, 1 KEVIN A. KEAY, 1,2 * KATHERINE PODZEBENKO, 1 BRENT D. GORDON, 1 AND RICHARD BANDLER 1,2 1 Department of Anatomy and Histology, The University of Sydney, Sydney, New South Wales 2006, Australia 2 Pain Management and Research Centre, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia ABSTRACT Studies utilizing the expression of Fos protein as a marker of neuronal activation have revealed that pain of deep somatic or visceral origin selectively activates the ventrolateral periaqueductal gray (vlPAG). Previous anatomical tracing studies revealed that spinal affer- ents to the vlPAG arose from the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus at all spinal segmental levels, with approximately 50% of vlPAG- projecting spinal neurons found within the upper cervical spinal cord. This study utilized detection of Fos protein to determine the specific populations of vlPAG-projecting spinal neurons activated by noxious deep somatic or noxious visceral stimulation. Pain of cardiac or peritoneal (i.e., visceral) origin activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the thoracic cord, whereas pain of hindlimb (i.e., deep somatic) origin activated neurons in the same laminar regions but in the lumbosacral cord. Each of these deep noxious manipulations also activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the upper cervical spinal cord. In a second set of experiments, the combination of retrograde tracing and Fos immunohistochem- istry revealed that vlPAG-projecting spinal neurons activated by deep somatic pain were located in both the upper cervical and lumbosacral cord, whereas those activated by visceral pain were restricted to the thoracic spinal cord. Thus pain arising from visceral versus deep somatic body regions influences neural activity within the vlPAG via distinct spinal path- ways. The findings also highlight the potential significance of the upper cervical cord in integrating pain arising from deep structures throughout the body. J. Comp. Neurol. 425: 323–344, 2000. © 2000 Wiley-Liss, Inc. Indexing terms: visceral pain; somatic pain; superficial dorsal horn; lateral spinal nucleus; c-Fos More than 50 years ago Sir Thomas Lewis (1942) called attention to the fact that the response to pain of deep origin (muscle, joint, viscera) was distinct from the re- sponse evoked by superficial (cutaneous) pain. He noted that deep pain characteristically evoked a passive emo- tional coping style of response consisting of behavioural quiescence, decreased reactivity to the environment, hy- potension, bradycardia, sweating, and nausea, whereas cutaneous pain evoked an active emotional coping re- sponse of agitation, hyper-reactivity, fight-flight, hyper- tension, and tachycardia. The passive vs. active coping reactions evoked respectively by deep vs cutaneous pain were so different that Lewis suggested they indicated the existence of distinct central processing channels: The difference in the qualities of skin pain and of deep pain is so clear and each belongs so exclusively to the corre- Grant sponsor: NHMRC Australia; Grant number: 970688. *Correspondence to: K.A. Keay, Department of Anatomy and Histology, F13, University of Sydney, NSW 2006, Australia. E-mail: keay@anatomy.usyd.edu.au Received 18 February 1999; Revised 27 April 2000; Accepted 2 June 2000 THE JOURNAL OF COMPARATIVE NEUROLOGY 425:323–344 (2000) © 2000 WILEY-LISS, INC.