In the present study, we classified DRG neurons into 4 clusters according to the expression patterns of OXT and its related receptors using single-cell real-time PCR. Cluster 1 was characterized mainly by the high expression of Piezo2, Cluster 2 by TRPV1, and Cluster 4 by OXTR. Whereas Cluster 1 contained cells with a wide range of diameters, OXT-expressing cells were found to be the large cells in the cluster. In particular, the OXT-expressing DRG neurons with large-diameter cell bodies (Cluster 1) may correspond to neurons of Aβ fibers (mechanoreception) and the OXT-expressing DRG neurons with small-diameter cell bodies (Cluster 2) may correspond to neurons of C fibers (nociception).

The DRG neurons classified as Cluster 2 in the present study highly expressed TRPV1 and were supposed to possess unmyelinated C fibers. As it has been shown that OXT acts directly on TRPV1 [16], it is possible that the analgesic effect of OXT is exerted by alleviating the perception of pain transmitted through the activation of DRG neurons in Cluster 2.

In the present study, some cells in Cluster 2 showed co-expression of V1aR and TRPV1. Han and colleagues showed that OXT significantly increased potassium conductance via V1a receptors in DRG neurons using the whole cell patch clamp recording. They considered that analgesic effects produced by peripheral administration of OXT were attributable to the activation of V1a receptors, resulting in reduction of TRPV1 activity and enhancement of potassium conductance in DRG neurons [11]. Thus, the analgesic effects of OTX via activation of V1aR may occur in DRG neurons that are classified as Cluster 2.

In terms of peripheral OXT secretion, our results demonstrated that OXT-expressing neurons contain Piezo2 in addition to TRPV1 for the first time, suggesting that not only nociception but also mechanical stimulation can induce OXT secretion in the DRGs. Taken together, in the DRGs, OXT should be released by mechanoreception and nociception, acting on non-myelinated C fibers to relieve pain. The pain-relief effects of massage or patch adhesion [21] could be via this peripheral action of OXT.

The following results may provide some suggestions about the peripheral action of OXT. Saito and colleagues showed the effectiveness for 300 patients of pyramidal thorn patch adhesion on pain regions as a complementary medicine, resulting that patch adhesion can induce pain relief [21]. Their interpretation for the effects of patch adhesion was as follows. The pathological pain signal appears in the normal peripheral tissue and in nerves that activate Aδ fiber high-threshold mechanoreceptors and C fibers [22]. This pain signal is considered to be reduced by gentle mechanical stimulation of the skin (e.g., application of pyramidal thorn patches) that activates Aβ fiber low-threshold mechanoreceptors [22, 23]. The interaction between the nociceptive signal (Aδ and C fibers) and the non-nociceptive signal (Aβ fibers) was introduced as the gate control theory of pain [24, 25]. The gate control theory hypothesizes that non-nociceptive input closes the gates to nociceptive input, which prevents pain sensations from traveling to the central nervous system. Therefore, Aβ fibers are considered to inhibit the effects of the firing of Aδ and C fibers. Our present findings suggested that Cluster 1 DRG neurons, probably corresponding to Aβ-fiber neurons, may release OXT following to mechanical stimulation regardless of nociception. That is, mechanical stimulation is considered to release OXT, resulting in alleviation of pain.

As described in Introduction, OXT is well known to be also synthesized and to function in the brain. OXT is synthesized in neurons of the supraoptic nucleus and paraventricular nucleus of the hypothalamus after specific stimulation of the brain. These neurons project to the posterior pituitary, where OXT is released into the blood for delivery to peripheral tissues as well as into the brain. Many researchers have strongly believed that the effect of OXT on pain relief can be controlled by this central OXT. In the brain, OXTergic antinociception is thought to be mediated by GABAergic interneurons that inhibit the primary nociceptive inputs conveyed by Aδ and C fibers to the spinal cord [26, 27]. The involvement of GABA mediated by OXT in pain relief was also confirmed in newborn rats [28]. Furthermore, the involvement of V1aR was found using knock-out mice, because OXTR knock-out mice displayed a pain phenotype identical to wild-type mice, whereas OXT-induced analgesia was completely absent in V1aR knock-out mice [29]. These mysterious phenomena may be caused by an unknown cross-talk reaction between the OXT and V1a systems.

Previous studies have suggested that humans and other mammals feel comfort (i.e., pleasure) when the perception of mild skin stimulation is sent to the brain via C fibers [30, 31]. It is possible that, in such a situation, OXT is released not only from the hypothalamus but also in the DRG. It will be interesting to see how the central and local actions of OXT interact with each other in future studies.

About the cell size of DRG neurons, the researchers discuss it through relative comparisons, using the terms like large diameter or small diameter. For example, measuring the cell size in stained tissues [32] and measuring the cell size after isolating in our present study are fairly different. The size also depends on the development of mouse. In other words, the ‘relative’ size is important for DRG neurons.

Finally, even though it can be considered that Cluster 1 DRG neurons, probably corresponding to Aβ-fiber neurons, may release OXT following to mechanical stimulation, such as adhesion of pyramidal thorn patches [21], regardless of nociception in the DRG, direct evidence about the release of OXT and the physiological function of OXT in the DRG has not been demonstrated. Thus, in the next study, we should show that mechanoreception and nociception themselves induce the autocrine/paracrine function of OXT in the DRG, and that OXT interferes the pain signal.

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