Welcome to the Section on Functional Neuroanatomy
National Institute of Mental Health
National Institutes of Health, DHHS
Miles Herkenham, Ph.D., Chief
Cannabinoid and Opioid Receptor Localization Studies
|Techniques for localizing receptors recognized by neurotransmitters and psychoactive drugs were developed earlier in this laboratory. Brain maps of opioid (e.g. morphine) and cannabinoid (e.g. cannabis: marijuana) receptor distribution have been published. Opioid receptors are found in all parts of the brain, notably in sensory waystations and areas that control emotion (hypothalamus and amygdala), cognition (cerebral cortex), and pleasure (ventral forebrain). Cannabinoid receptors are localized in areas that control movement (basal ganglia, cerebellum), cognition (cerebral cortex), and attention and memory (hippocampus; see picture below). Cannabinoid receptors are notably sparse in areas that control heart rate and respiration (medulla), explaining why there are not fatal overdoses of marijuana. Cannabinoid|
|receptors are also located in areas that control emesis (nucleus of the solitary tract) and pain (see bottom),
suggesting medical potential of marijuana. Receptors are not localized on ventral forebrain dopamine neurons that are implicated in abuse potential of psychoactive drugs, so effects of marijuana on "reward" systems are indirect.
Herkenham, M. and Pert, C. B. In vitro autoradiography of opiate receptors in rat brain suggests loci of "opiatergic" pathways. Proc. Natl. Acad. Sci. U.S.A. 77: 5532-5536, 1980.
Herkenham, M. and Pert C. B. Light microscopic localization of brain opiate receptors: a general autoradiographic method which preserves tissue quality. J. Neuroscience 2: 1129-1149, 1982.
Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC: Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA 87:1932-1936, 1990.
Herkenham M: Localization of cannabinoid receptors in brain and periphery; in: Pertwee RG (ed): Cannabinoid Receptors. New York, Academic Press, 1995, pp. 145-166.
Brady, L.S., Herkenham, M. Rothman, R.B., Partilla, J.S., Kšnig, M. Zimmer, A.M., and Zimmer, A. Regionally specific up-regulation of mu and delta opioid receptor binding in enkephalin knockout mice. Mol. Br. Res. 68: 193-197, 1999.
Cannabinoid receptors as therapeutic targets: pain pathways.
|Electrophysiological, neurochemical, and behavioral studies have shown that cannabinoids (marijuana-like drugs) suppress pain neurotransmission. To address the underlying mechanism, we have identified the locations of cannabinoid receptors in primary pain pathways using the techniques of in situ hybridization histochemistry and in vitro receptor binding/autoradiography. Central cannabinoid CB1 receptors are synthesized in cells of the dorsal root ganglia (see picture at left) and inserted on terminals in the spinal cord. In the dorsal root ganglia, identifying which cells carry pain information is achieved by labeling for substance P mRNA (marker of nociceptive cells). In double-label experiments, we have determined that only a small fraction of substance P-positive cells also expresses CB1 mRNA. Furthermore, in the spinal cord where the nerve rootlets terminate in the dorsal|
| horn, only a portion of cannabinoid receptors is found presynaptically on central terminals of primary afferents, and the remainder is located on processes of the spinal cord itself. We think that these results have implications for how cannabinoids may work in chronic pain states. A differential anatomical basis underlying cannabinoid and mu opioid modulation of primary afferent transmission is supported. Whereas mu opioid receptors in spinal cord are associated predominantly with thin-diameter primary afferents, cannabinoid receptors are localized to both thin and coarse diameter fibers. These differences may provide a basis for the possibility that cannabinoids may relieve pain when traditional opiate drugs fail.
Hohmann, A. G., Briley, E. M., and Herkenham, M. Pre- and post-synaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Research, 822: 17-25, 1998.
Hohmann, A.G. and Herkenham, M. Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment. Neurosci. Lett., 252: 13-16, 1998.
Hohmann, A. G. and Herkenham, M. Localization of cannabinoid receptor CB1 mRNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neuroscience, 90: 923-931, 1999.
Hohmann, A. G. and Herkenham, M. Cannabinoid receptors undergo axonal flow in sensory nerves. Neurosicence, 92: 1171-1175, 1999.