GHRP-2, a synthetic agonist of the ghrelin receptor, has been found to modulate pain in animals without increasing rates of addiction via interaction with the central opioid system. This is the same system by which drugs like Oxycontin and hydrocodone ect.
Scientific studies based on animal test subjects have been able to determine that GHRP-2 has also been found to increase the effects of opioid medications, improving their potency and more importantly reducing long-term addictive effects.
GHRP-2 and GHRP-6 have long been associated with improved joint pain in animal test subjects with osteoarthritis. This was originally attributed to the molecule’s ability to increase growth hormone (GH) levels within the animal test subject. (GH can accelerate healing). What was interesting, however, was that GHRP-2 produced pain relief long before any healing could take place. This suggested that GHRP-2 was working to relieve pain through some other mechanism. It was eventually discovered that GHRP-2 interacts with opioid receptors.
The Opioid Receptors and Addiction
There are four major opioid receptors (DOR, KOR, MOR, and NOP) as well as several minor variants within each major category. The properties of opioid medications are determined by how strongly they bind to each of the receptors as follows.
. DOR – pain relief (analgesia) and addiction.
. KOR – analgesia and sedation, but not addiction.
. MOR – analgesia, addiction, and respiratory depression (decrease in breathing).
. NOP – appetite loss and changes in tolerance to opioids.
Most opioid medications are non-discriminate binders, meaning they tend to bind to all four receptors and thus produce a wide range of effects. This is why all opioid medications have a potential for addiction. GHRP-2, however, appears to be different. GHRP-2 has strong proclivity for the DOR and KOR receptors and almost no affinity for the MOR receptor .
Given that the MOR receptor is the one most strongly associated with the negative side effects of opioids (addiction, respiratory depression, constipation), GHRP-2 may be able to offer pain relief without many of the risks of other opioid drugs. Though the DOR receptor is associated with addiction, animal studies suggest that low-level DOR binding may actually counteract some of the effects associated with MOR binding and thus combat addictive potential .
While GHRP-2 is known to increase the effects of opioid medications, GHRP-6 has been found to decrease their effects . This indicates that the role of ghrelin and its synthetic analogues in pain relief is likely modulated by more complex receptor interactions than are currently understood. Whatever the case may be, ongoing research is continuing to demonstrate unique benefits of synthetic peptide secretagogues like GHRP-2.
 P. Zeng, S. Li, Y. Zheng, F.-Y. Liu, J. Wang, D. Zhang, and J. Wei, “Ghrelin receptor agonist, GHRP-2, produces antinociceptive effects at the supraspinal level via the opioid receptor in mice,” Peptides, vol. 55, pp. 103-109, May 2014.
 Y. F. Su, R. W. McNutt, and K. J. Chang, “Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception,” J. Pharmacol. Exp. Ther., vol. 287, no. 3, pp. 815-823, Dec. 1998.
 P. Zeng, J.-X. Chen, B. Yang, X. Zhi, F.-X. Guo, M.-L. Sun, J.-L. Wang, and J. Wei, “Attenuation of systemic morphine-induced analgesia by central administration of ghrelin and related peptides in mice,” Peptides, vol. 50, pp. 42-49, Dec. 2013.