Early life nociception is influenced by peripheral growth hormone signaling

Abstract

A number of cellular systems work in concert to modulate nociceptive processing in the periphery, but the mechanisms that regulate neonatal nociception may be distinct compared to adults. Our previous work indicated a relationship between neonatal hypersensitivity and growth hormone (GH) signaling. Here, we explored the peripheral mechanisms by which GH modulated neonatal nociception under normal and injury conditions (incision). We found that GH receptor signaling in primary afferents maintains a tonic inhibition of peripheral hypersensitivity. After injury, a macrophage dependent displacement of injury-site GH was found to modulate neuronal transcription at least in part via serum response factor regulation. A single GH injection into the injured hindpaw muscle effectively restored available GH signaling to neurons and prevented acute pain-like behaviors, primary afferent sensitization, neuronal gene expression changes, and the long-term somatosensory changes observed after repeated peripheral insult. These results may indicate a novel mechanism of neonatal nociception.

Optogenetic Early Life Pain leads to cortical hyperexcitability, nociceptive hypersensitivity and repetitive behavior

“…The resulting neuroimmune activation 6, 7 and low endocannabinoid tone 5 may predispose to metabolic disease or reward de ciency syndromes 66 . The present study is the rst that addresses early life pain without injury, an important difference, because the tissue response to the injury per se may prime the neuroimmune system 7,67 and was shown to result in a macrophage-dependent sequestration of growth hormone 21 .…”

“…The results mostly show that such neonatal injuries increase nociceptive sensitivity in adult life and cause a more serious course of a second injury in adult life 7,20,21 . The resulting neuroimmune activation 6, 7 and low endocannabinoid tone 5 may predispose to metabolic disease or reward de ciency syndromes 66 .…”

“…Previous studies have employed repeated pin prick 18 , skin incision 16,19,21,65 or nerve injury 6 of neonatal mice or rats to assess the impact of early life pain.…”

“…Transcriptomic changes would agree with fewer synaptic contacts possibly owing to a higher rate of neuronal apoptosis 10,79 and re nement of neuronal networks that were highly in use upon pain stimulation 9 . In the context of early life injuries such as skin incision, such priming was shown to increase the response to injuries in later life 20,21 , a phenomenon that is believed to involve central sensitization and immune activation. It is important to note, that our mice did not receive an injury at any time, and transcriptomics reveal that blue light exposure did not elicit neuroin ammation that was described in neonatal injury models 6, 7 .…”