Historically, in 1981, growth hormone-releasing peptides (GHRPs) initially were thought to re fl ect the actions of elusive GHRH but fortunately in 1982 GHRH was isolated. By 1984 GHRP-6 results revealed that the actions of GHRH and GHRP were distinguishable from each other. To appreciate GHRP and GHRH interrelationships on GH release, detailed in vitro and in vivo dose-response studies were essential. Over subsequent years GHRPs were studied by many talented basic and clinical investigators. By 1995 GHRP icv administration was found to increase food intake in conscious rats and in 1996 the GHS-1a receptor was cloned. Finally, in 1999 the GHRP/GHS natural hormone, ghrelin, was isolated, synthesized, and found to have essentially the same activity as that of GHRPs/GHSs in animals and humans. A major surprise and a reorienting fi nding was the primary anatomical location of ghrelin in the stomach and, in addition, strong enhancement of food intake. Over time, GH secretion has been hypothesized to be primarily regulated by the hypothalamic hypophysiotropic tripartite system of GHRH, ghrelin, and SRIF rather than the bipartite system of GHRH and SRIF. Since the isolation of ghrelin, actions of this hormone have continued to expand from the hypothalamic CNS to peripheral sites. This includes both direct and indirect actions particularly related to nutrition and metabolism as well as a cornucopia of unexpected actions. In summary, unnatural GHRP begot natural ghrelin and its receptor. This reverse pharmacology approach forecasts that variations of the unnatural to natural sequence of events likely will be more frequent, modi fi ed, expanded, and re fi ned in the future.
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