Abstract
Piezo2 is a mechanically gated ion-channel that has a well-defined role in innocuous mechanical sensitivity, but recently has also been suggested to play a role in mechanically induced pain. Here we have explored a role for Piezo2 in mechanically evoked bone nociception in Sprague Dawley rats. We have used an in vivo electrophysiological bone-nerve preparation to record the activity of single Aδ bone afferent neurons in response to noxious mechanical stimulation, after Piezo2 knockdown in the dorsal root ganglia with intrathecal injections of Piezo2 antisense oligodeoxynucleotides, or in control animals that received mismatch oligodeoxynucleotides. There were no differences in the number of Aδ bone afferent neurons responding to the mechanical stimulus, or their threshold for mechanical activation, in Piezo2 knockdown animals compared to mismatch control animals. However, bone afferent neurons in Piezo2 knockdown animals had reduced discharge frequencies and took longer to recover from stimulus-evoked fatigue than those in mismatch control animals. Piezo2 knockdown also prevented nerve growth factor (NGF)-induced sensitization of bone afferent neurons, and retrograde labeled bone afferent neurons that expressed Piezo2 co-expressed TrkA, the high affinity receptor for NGF. Our findings demonstrate that Piezo2 contributes to the response of bone afferent neurons to noxious mechanical stimulation, and plays a role in processes that sensitize them to mechanical stimulation.
Highlights
Pain associated with bone marrow edema syndromes, osteomyelitis, osteoarthritis, fractures, and bone cancer puts a significant burden on individuals, society, and health care systems worldwide
Aδ bone afferent neurons recorded from animals administered Piezo2 antisense ODNs had reduced activity in response to pressure applied to the marrow cavity, compared to those recorded from mismatch control animals (Figures 2A,B)
There were no differences in the number of discriminable Aδ bone afferent units responding to the pressure stimulus [ANOVA, P > 0.05, n = 23naïve/31 mismatch/n = 35 antisense, N = 10 naïve/15 mismatch/21 antisense; Figure 2F], or their threshold for mechanical activation [mixed model, F (6.139), DFn(2), Dfd(45), Dunnett’s P > 0.05; n = 23 naïve/31 mismatch/35 antisense, N = 10 naïve/15 mismatch/21 antisense; Figure 2G], in recordings made from Piezo2 knockdown compared to mismatch control animals
Summary
Pain associated with bone marrow edema syndromes, osteomyelitis, osteoarthritis, fractures, and bone cancer puts a significant burden (both in terms of quality of life and cost) on individuals, society, and health care systems worldwide. The identity of molecules that transduce noxious mechanical stimuli in bone, and/or influence the mechanical sensitivity of bone nociceptors, has not yet been established. This has limited our understanding of how nociceptors. Piezo knockdown in dorsal root ganglia (DRG) inhibits inflammation-induced mechanical but not thermal hyperalgesia in mouse skin (Singhmar et al, 2016) and attenuates viscero-motor pain reflexes in response to noxious and innocuous colorectal distension in rats (Yang et al, 2016b). Piezo knockout does not prevent cutaneous nociceptors from transducing mechanical stimuli but it does reduce the sensitivity of mechano-nociceptors in the skin-nerve preparation (Ranade et al, 2014; Murthy et al, 2018). Previous studies have identified interactions of Piezo with other proteins, for example nerve growth factor (NGF), that together contribute to the mechanical sensitivity of peripheral sensory neurons (Qi et al, 2015; Prato et al, 2017)
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