Injecting ghrelin into specific brain regions significantly reduced pain responses in rats while increasing levels of the body's natural painkilling peptides, beta-endorphin and met-enkephalin.
Significant pain reduction (p<0.01)Ghrelin injected into two different brain regions reduced pain across all phases of testing while boosting the brain's own opioid peptides
What the researchers found
Both intracerebroventricular (ICV) and intra-arcuate nucleus (ARC) injection of ghrelin significantly reduced pain behavioral scores across all phases of the formalin test (p < 0.01). Simultaneously, concentrations of met-enkephalin (MENK) and beta-endorphin (β-EP) in the periaqueductal gray area increased significantly following ghrelin injection. This demonstrates that ghrelin's pain-relieving effect operates through the arcuate nucleus and involves activation of the endogenous opioid system.
Why it matters
Understanding how peptides like ghrelin interact with the brain's natural pain pathways could lead to new, non-addictive pain treatments. Current opioid painkillers carry serious risks of addiction and overdose. If ghrelin or similar peptides can activate the body's own opioid system in a controlled way, they might offer pain relief with a better safety profile than synthetic opioids.
How the study worked
Thirty-five male rats were divided into five groups. Ghrelin was injected into either the left lateral ventricle (ICV, 5 µL) or the arcuate nucleus (ARC, 1 µL). Fifteen minutes later, formalin (2.5%) was injected into the left hind paw to induce pain. Behavioral pain scores were recorded for 60 minutes. Levels of met-enkephalin and beta-endorphin were collected from the periaqueductal gray area using microdialysis and measured by high-performance liquid chromatography (HPLC).
What this study cannot tell us
This is an animal study in rats, and results may not directly translate to humans. The ghrelin was injected directly into the brain, which is not a practical clinical delivery method. The sample size of 35 rats across 5 groups (7 per group) is relatively small. The formalin test models acute inflammatory pain but does not capture chronic pain conditions. Long-term effects and potential side effects of brain ghrelin injection were not assessed.
How to read the evidence
This is a preclinical animal study with a small sample size (n=35 rats). While the results are statistically significant and mechanistically informative, they represent early-stage evidence that requires validation in larger animal studies and eventually human trials.
When this study was published
Published in 2019, this study builds on growing interest in ghrelin's non-metabolic functions. The findings remain relevant as peptide-based pain management continues to be an active research area.
The bigger picture
Ghrelin is best known as the 'hunger hormone,' but research increasingly reveals its roles in pain modulation, mood, and neuroprotection. This study adds mechanistic evidence that ghrelin's pain-relieving effects work through the endogenous opioid system — the same system targeted by morphine and other opioid drugs. Understanding this pathway at a peptide level could inform the development of targeted peptide therapies that harness natural pain relief mechanisms without the risks of traditional opioids.
Questions still open
- Could peripherally administered ghrelin or ghrelin receptor agonists achieve similar pain-reducing effects without direct brain injection?
- Does chronic ghrelin-based pain modulation carry risks of tolerance or dependence similar to exogenous opioids?
- How does ghrelin's analgesic effect compare in magnitude to conventional opioid analgesics?
Common questions
What is ghrelin and what does it normally do?
How could this research lead to new pain treatments?
Read the original research
Effects of Intracerebroventricular and Intra-Arcuate Nucleus Injection of Ghrelin on Pain Behavioral Responses and Met-Enkephalin and β-Endorphin Concentrations in the Periaqueductal Gray Area in Rats.
International journal of molecular sciences, 20(10)
Citation
Pirzadeh, Samaneh; Sajedianfard, Javad; Aloisi, Anna Maria; Ashrafi, Mahboobeh. (2019). Effects of Intracerebroventricular and Intra-Arcuate Nucleus Injection of Ghrelin on Pain Behavioral Responses and Met-Enkephalin and β-Endorphin Concentrations in the Periaqueductal Gray Area in Rats.. International journal of molecular sciences, 20(10). https://doi.org/10.3390/ijms20102475