Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation

Abstract

Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRGs). However specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. GH modulates homeostasis and tissue repair after injury, but how GH effects nociception in neonates is not known. To determine if GH played a role in modulating sensory neuron function and hyper-responsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skin-saphenous nerve-dorsal root ganglion (DRG)-spinal cord preparation. Results show that inflammation of the hairy hindpaw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated via an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that following GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRGs.

Early life nociception is influenced by peripheral growth hormone signaling

“…However, evidence suggests that there is also a peripheral component that has been less explored (Moriarty et al, 2018). We have shown that the pattern of primary afferent sensitization and injury-related receptor/channel expression in the DRGs after neonatal peripheral injury is unique to that observed in adult nociceptors (Jankowski et al, 2014) (Liu et al, 2017) (Ye and Woodbury, 2010) (Koerber et al, 2010) (Koerber and Woodbury, 2002). Altogether, this suggests that the mechanisms of nociception in neonates may be somewhat distinct.…”

“…The largest increases in systemic GH levels are known to occur during early postnatal development, which corresponds with the most rapid growth period (Bartholomew EF, 2009). This is the same developmental period when GH was found to substantially influence pain-like responses and primary afferent function (Liu et al, 2017) (Ford et al, 2019). Specifically, inflammatory nociception was correlated with a reduction of site-specific cutaneous GH levels that could be prevented by systemic GH treatment.…”

“…Injection of GH into the muscles after incision specifically blocked the injuryrelated upregulation of SRF and STAT5. Since genetic knockout of GHr in uninjured sensory neurons regulated SRF expression (above) and to determine the role that one of these factors may play in muscle incision-induced hypersensitivity in neonates, we utilized our in vivo nervetargeted siRNA knockdown strategy to inhibit the DRG upregulation of SRF (Jankowski et al, 2009) (Liu et al, 2017). Prior to incision, animals were injected with Penetratin-linked siRNAs against SRF (PenSRF) into the right sciatic nerve.…”

“…We recently found that growth hormone (GH) may be one factor involved in generalized painrelated responses to peripheral injury in neonates (Liu et al, 2017) (Ford et al, 2019). The pituitary gland generates GH, which is crucial for normal growth and development.…”

“…Specifically, inflammatory nociception was correlated with a reduction of site-specific cutaneous GH levels that could be prevented by systemic GH treatment. These effects may have been due to direct GH modulation of receptor/channel expression in neonatal DRGs (Liu et al, 2017) (Ford et al, 2019).…”