The results of the present study demonstrate that ghrelin has hiperalgesic effect in mice. This is only a preliminary study and no attempt was made to clarify the possible mechanism of action of ghrelin on pain threshold. This is the one possibility that ghrelin may induce the Ca
2+ entry into the neuronal tract involved in transporting noxious stimuli. There is not any direct evidence about this insight. However, ghrelin induces an increase in the intracellular calcium concentration in porcine somatotropes via L-type calcium channel in a dose dependent manner
13. In a zero Na
+ solution, the stimulatory effect of ghrelin on somatotropes was decreased, suggesting that besides calcium channel, sodium channels are also involved in ghrelininduced calcium transients
13. Additionally, ghrelin directly interacts with NPY neurons in the arcuate nucleus to induce Ca
2+ signalling via protein kinase-A and N-type calcium channel-dependent mechanisms in rats
14.
Histaminergic neurons in the tuberomamillary nucleus are implicated in nociception 15 and presence of GHS-R in the tuberomammillary nucleus was suggested by the existence of GHSR mRNA in this area 7. Therefore ghrelin may show its nociceptive effect indirectly by affecting histaminergic transmission. In an electrophysiologic study, it is demonstrated that ghrelin activates histaminergic neurons in the tuberomammillary nucleus by inhibiting G protein-coupled inwardly rectifier K+ channels 16. Injection of histamine into the rat dorsal raphe nucleus and periaqueductal grey region produces an antinociception, while its injection into the median raphe nucleus causes hyperalgesia 17,18. Intracerebroventricular administrations of low doses of histamine elicit hyperalgesia, while high doses of histamine produce antinociception 19,20. The results of above studies suggest that the opposite effects of histamine on pain threshold may be mediated through different subtypes of histamine receptors 20,21.
It is presented that serotonergic pathways originating from dorsal raphe nucleus is involved in pain modulation 22. Raphe nucleus is another target for the effect of ghrelin 9. Ghrelin has been found to decrease serotonin release in hypothalamus in vitro 23 and suggested to decrease serotonin release in dorsal raphe nucleus 24, which may have an additional role in food intake-increasing effect of ghrelin. Therefore, ghrelin may also affect analgesic system due to its effects on serotonergic transmission in brain stem, which also modulates pain transmission in medulla spinalis.
In conclusion, ghrelin may be a candidate for hormonal regulation of pain sensitivity. However, further studies are needed to establish its effect on nociception and the mechanism by which it exerts its effect.