In mice, a tiny piece of the hormone ghrelin (called ghrelin(1‑7)-NH2) reduces pain when it’s injected directly into the brain. The pain‑killing effect works through the ghrelin receptor and also taps into the body’s own opioid system, boosting natural pain‑relief chemicals. While this shows the fragment can act as an analgesic, the way it was given (into the brain) isn’t something you can safely do at home.

Ghrelin(1-7)-NH₂ is the active N-terminal hepta-peptide of ghrelin as an agonist at the ghrelin receptor GHS-R1α. The biological functions of ghrelin(1-7)-NH₂ have not been well investigated. Therefore in this study, we were interested in exploring the effects and molecular mechanisms of ghrelin(1-7)-NH₂ in pain modulation at the supraspinal level using the tail withdrawal test in mice. Intracerebroventricular (i.c.v.) injection of ghrelin(1-7)-NH₂ (0.002, 0.02, 0.2 and 2 nmol/kg) induced a dose- and time-related antinociceptive effect. This antinociceptive effect was fully antagonized by co-injection with the GHS-R1α antagonist [D-Lys³]-GHRP-6, indicating that this effect induced by ghrelin(1-7)-NH₂ was mediated through the activation of GHS-R1α. Interestingly, naloxone, β-funaltrexamine, naloxonazine, and naltrindole, but not nor-binaltorphimine, could also antagonize the antinociceptive effect markedly, suggesting that OPRM (primary μ₁ subtype) and OPRD were involved in the antinociceptive response induced by ghrelin(1-7)-NH₂. Furthermore, the qRT-PCR and Western blot results indicated that both mRNA and protein levels of PENK and OPRD were up-regulated significantly. Using the fluorescence labeling method, our results showed that ghrelin(1-7)-NH₂ (i.c.v.) was mainly distributed at the dorsal 3rd ventricle and hippocampus where there are regions with high expressions of ghrelin, GHS-R1α and ORs. All these results indicated that ghrelin(1-7)-NH₂ initially activated the GHS-R1α, then activated the OPRM, as well as increased the release of endogenous PENK to activate of OPRD to produce antinociception. These results contributed to understanding the mechanisms of antinociception induced by ghrelin(1-7)-NH₂. Furthermore, ghrelin(1-7)-NH₂ as the active fragment of ghrelin may be a promising peptide for developing new analgesic drugs.