Essentially a synthetic version of ghrelin analogue, GHRP-2 stimulates the release of an endogenous growth hormone (GH) within the somatotropes of the anterior pituitary in the animal and human body. Specifically, GHRP-2 will increase the number of somatotropes in a GH pulse by limiting the amount of somatostatin present, while standard GHRH increases the amplitude at which the pituitary cells pulse.
Unlike ghrelin, GHRP-2 is not specifically used to increase appetite, but it may have secondary actions that impact hypothalamic neurons. These effects last for approximately an hour after the initial application, which mimics the natural application of GH and consists of an eight hour circulation period.
The most important initial historical time points in the development of the enlarging ghrelin system were 1973, 1976, 1982, 1984, 1990, 1996, 1998, and 1999 during which the following sequentially occurred:1
- isolation of somatostatin, discovery of unnatural growth-hormone-releasing peptides (GHRPs)
- isolation of growth-hormone-releasing hormone (GHRH)
- hypothesis of a new natural GHRP different from GHRH
- GHRP+GHRH synergism in humans
- discovery of the growth hormone secretagogue GHS/GHRP receptor
- cloning of the receptor
- isolation and identification of the new natural endogenous GHRP ghrelin
Thanks to the assiduousness of talented researchers around the globe, our contemporary understanding of the pharmacology and probably also the physiological regulation of growth hormone secretion, came about after the important discovery that GHRP increased pulsatile GH secretion in not only children, but also within normal younger and older men and women. Even though GHRP alone substantially releases GH from the pituitary in vitro without the addition of GHRH, this rhythmic endogenous secretion does require some GHRH.
GHRP was first envisioned to be an analog of GHRH but, from comparison of the activity of GHRH and GHRPs between 1982 and1984, it was hypothesized to reflect the activity of a new hormone regulator of GH secretion yet to be isolated and identified. Intravenous bolus GHRP releases more GH than GHRH in humans, but the reverse occurs in vitro. GHRPs are pleiotropic peptides with major effects on GH, nutrition, and metabolism, especially as an additional hormone in combination with GHRH as a new regulator of pulsatile GH secretion. The first indication of pleiotropism was an increase of food intake by GHRP. A major reason for the prolonged initial interest in the GHRPs has been its similar, yet different and complementary, action with GHRH on GH regulation and secretion.
Particularly noteworthy is the variable chemistry of the GHRPs. They consist of three major chemical classes including peptides, partial peptides, and nonpeptides, and all appear to act via the same receptor and cellular mechanisms. Generally, most GHRPs have been active by all routes of administration, namely intravenously (IV), subcutaneously (SC), orally, intranasally, and intracerebroventricularly (IVC), which supports their possible broad future clinical utility. From evolutionary studies starting with the zebrafish, the natural receptor and hormone have been present for hundreds of years, underscoring the fundamental evolutionary and functional importance of the ghrelin system. GHRPs were well established to act directly on both the hypothalamus and pituitary several years before the GHS receptor assay.23
Finally, the ghrelin chemical isolation and identification was accomplished surprisingly from the stomach, which is the major site but not the only site. Ghrelin was isolated and identified.4 A primary action of GHRPs continues to concern GH secretion and regulation, but increasingly this has included direct and indirect effects on nutrition and metabolism, as well as a variety of other actions which may be pharmacological and/or physiological.
Does GHRP-2 Work?
The below study results demonstrate the actions of GHRP-2 and GHRP-6 on GH releases in pituitary cells, and a follow up study which focused on increasing these concentrations to create GH dependency to better understand potential dosing restrictions, should this chemical be used in therapeutic sessions in the future:
- GHRP-2, GHRP-6 and GRF were applied in increasing concentrations to partially purified sheep somatrophs to cause a release of growth hormone in a dependent manner. GHRP-6 was not found to increase the cAMP levels. Mixtures of GRF and GHRP-2 were found to increase growth hormone and cAMP levels, but a combination of GHRP-2 and GHRP-6 did not.
- When the cells were pretreated with an adenylyl cyclase inhibitor, they did not see a cAMP increase, though there was a growth hormone increase when GRF or GHRP-2 were applied. This antagonist did not prevent cAMP reactions when a combination of growth hormone and GHRP-6 was applied.
- When the antagonist was applied to the growth hormone receptor, the GHRP-2 and GRF combination did not increase the cAMP rates, but prevented any release of growth hormone when GRF, GHRP-2, or GHRP-6 were applied.
- GHRP-2 has been demonstrated to affect the ovine pituitary somatotroph to increase cAMP concentrations in a way similar way that of GRF. However, GHRP-2, GHRP-6, and GRF all act on different receptors which explains why GHRP-6 did not have an effect cAMP levels on the rat pituitary cell cultures.
Food Intake & GH Release Effects
Research suggests that circulating ghrelin is also implicated in meal to meal regulation, wherein levels increase in anticipation of a meal and are suppressed by food ingestion, though the underlying mechanisms are not known.56
Serum ghrelin levels vary as a function of energy balance. Ghrelin levels are increased in anorexia and decreased in obesity.78 Thus, it is possible that ghrelin may be an important player in food intake behavior and perhaps in chronic over- and under-nutrition as well.9 Because of its dual effects, ghrelin may be a critical hormonal signal of nutritional status to the somatotropic axis, playing a role in integrating energy balance with the growth process.10
Additional studies demonstrate that peripheral administration of GHRP-2 increases food intake in humans. The effect of GHRP-2 is robust and elicited an increase of food intake in all subjects tested, all of which reported being hungrier while receiving GHRP-2. The magnitude of the effect of GHRP-2 on food intake (+35%) is comparable to that of ghrelin, previously shown to increase food intake by 28% in healthy subjects and by 31% in cancer patients.1112 The effect of 1 μg/kg/h of GHRP-2 is comparable to the effect of ghrelin (5 pmol/kg/min) not only on food intake, but also on GH release. In Wren's study (also in healthy lean subjects), ghrelin raised GH to similar levels (about 35 μg/L).13 Therefore, ghrelin or the ghrelin mimetic GHRP-2, when administered peripherally, is able to induce significant acute changes of similar magnitude in both GH levels and food intake behavior.
This suggests the possibility that the acute effect of GHRP-2 on food intake observed in some studies might result in a state of positive energy balance, were GHRP-2 administered chronically. Carefully designed and optimized chronic studies, including detailed body composition and food intake monitoring, will help to demonstrate the long-term effects of GHS(s) on food intake and body weight. Although GHRP-2 increased GH significantly, it is unlikely, judging from the results of rhGH alone, that this increase in GH levels is responsible for the acute changes in food intake in these studies.
A study focused on the proper administration of GHRP-2 on arthritic rats injected with Freund’s adjuvant, and then given daily exposures to GHRP-2 or ghrelin fifteen days later, returned interesting results:
- Those exposed to the ghrelin serum saw a decrease in their lepin concentrations
- Those given GHRP-2 saw ameliorated external symptoms of their arthritis and a decrease in their paw volume
- GHRP-2 also decreased IL-6 levels when they had originally been increased by the arthritis symptoms.
- The results of this study help to show that GHRP-2 may have use in managing IL-6 levels affected by arthritis. This further implies that GHRP-2 may have anti-inflammatory properties as the chemical appeared to have a positive effect on managing the ghrelin receptors and immune cells that were affected by the disease. The comparison of GHRP-2 to similar chemicals in a natural setting is ongoing to assist researchers in evaluating the similarities in composition, so the study of this chemical can be expanded to additional animals.
- 1. Methods Enzymol. 2012;514:3-32. History to the discovery of ghrelin. Bowers CY.
- 2. Science. 1996 Aug 16;273(5277):974-7. A receptor in pituitary and hypothalamus that functions in growth hormone release. Howard A.D., et al.
- 3. Mol Endocrinol. 1996 Jan;10(1):57-61. Identification of a new G-protein-linked receptor for growth hormone secretagogues. Pong SS1, Chaung LY, Dean DC, Nargund RP, Patchett AA, Smith RG.
- 4. Nature. 1999 Dec 9;402(6762):656-60. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Kojima M1, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K.
- 5. Diabetes. 2001;50:1714–1719. [PubMed] A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS.
- 6. J Clin Endocrinol Metab. 2002;87:1902–1906. [PubMed] Insulin, unlike food intake, does not suppress ghrelin in human subjects. Caixas A, Bashore C, Nash W, Pi-Sunyer FX, Laferrère B.
- 7. Eur J Endocrinol. 2001;145:669–673. [PubMed] Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Otto B, Cuntz U, Fruehauf E, Warwarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnart P, Fichter M, Tschop M.
- 8. Diabetes. 2001;50:707–709. [PubMed] Circulating ghrelin levels are decreased in human obesity. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML.
- 9. Regul Pept. 2002;105:75–81. [PubMed] Ghrelin-not just another stomach hormone. Wang G, Lee HM, Englander E, Greeley GH.
- 10. Topic Endocrinol Suppl. 2001;2:39–40. Ghrelin provides the calories that growth hormone requires for growth and repair. Heiman ML, Tschop M.
- 11. J Clin Endocrinol Metab. 2001;86:5992–5995. [PubMed] Ghrelin enhances appetite and increases food intake in humans. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR.
- 12. J Clin Endocrinol Metab. 2004;89:2832–2836. [PubMed] Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. Neary NM, Small CJ, Wren AM, Lee JL, Druce MR, Palmieri C, Frost GS, Ghatei MA, Coombes RC, Bloom SR.
- 13. Endocrinology. 2000;141:4325–4328. [PubMed] The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DC, Ghatei MA, Bloom SR.
- 14. J Pediatr Endocrinol Metab. 2003;16:981–985. [PubMed] Changes in appetite and body weight in response to long-term oral administration of the ghrelin agonist GHRP-2 in growth hormone deficient children. Mericq V, Cassorla F, Bowers CY, Avila A, Gonen B, Merriam GR.
- 15. J Clin Endocrinol Metab. 1998;83(4):1168–1172. [PubMed] Pharmacokinetics and pharmacodynamics of growth hormone-releasing peptide-2: a phase I study in children. Pihoker C, Kearns GL, French D, Bowers CY.