Effect of ghrelin signalling on mechanical and thermal sensitivity in healthy and diabetic mice

Introduction. Ghrelin exerts antinociceptive effects by mitigating inflammatory reactions and modulating neuronal activity in the spinal dorsal horn. Aims. We investigated the role of ghrelin and its receptor GHSR1a in modulating sensory behaviour in healthy and diabetic mice, and tested the hypothesis that ghrelin?s effect on sensory phenotype is associated with spinal microglial activity. Methods. Four week-old male C57BL/6 mice (WT) and double knockout (dKO) mice lacking both ghrelin and GHSR1a received single intraperitoneal injection of citrate buffer or streptozotocin (STZ) to induce diabetes. Glycaemia, mechanical threshold (von Frey hairs) and thermal sensitivity (tail immersion test) were measured weekly. At 8 postnatal weeks, animals were sacrificed and spinal microglia stained with anti-Iba1 antibody. Results. At 4 weeks, dKO mice showed an increased mechanical and thermal sensitivity compared to WT. However, while differences in thermal sensitivity disappeared with development, those in mechanical threshold increased. Interestingly, Iba1 stained a significantly smaller area in dKO spinal dorsal horn than in WT, implying an altered microglial phenotype. We asked whether such a difference was relevant for the development of pain hypersensitivity in diabetes. STZ-WT mice developed a strong hyperglycaemia associated with increased mechanical sensitivity. Surprisingly, STZ-dKO were more resistant to develop both hyperglycaemia and mechanical hypersensitivity. Conclusions. Our data support an antinociceptive role of ghrelin, which might involve microglia-neuron communication in the spinal dorsal horn. However, ablating ghrelin signalling does not worsen diabetes-induced hypersensitivity as it delays the onset of hyperglycaemia as well as diabetes-associated alterations in nociceptive behaviour.