Abstract:Pain on the body surface can accompany disorders in the deep tissue or internal organs. However, the anatomical and physiological mechanisms are obscure. Here, we provided direct evidence of axon bifurcation in primary C-nociceptive neurons that innervate both the skin and a visceral organ. Double-labeled dorsal root ganglion (DRG) neurons and Evans blue extravasation were observed in 3 types of chemically-induced visceral inflammation (colitis, urocystitis, and acute gastritis) rat models. In the colitis mode… Show more
“…One hallmark for inflammatory visceral pain manifestation is the development of referred cutaneous mechanical hypersensitivity (Bai et al, 2019; Bielefeldt et al, 2006; Bourdu et al, 2005; Cao et al, 2021; Gao et al, 2021; Jain et al, 2022; Laird et al, 2000; Laird et al, 2002; Lv et al, 2019; Traub et al, 2008; Zhou et al, 2008). Such referred hypersensitivity was also abolished in VGLUT3 Lbx1 -Abl mice, suggesting that VGLUT3 neurons must be part of previously proposed spinal circuits receiving convergent inputs from cutaneous and visceral afferents (Cervero, 2009; Cui et al, 2022; Fang et al, 2021; Fuentes and Christianson, 2018; Gebhart and Bielefeldt, 2016; Luz et al, 2015; Qiao and Tiwari, 2020). Thus, spinal VGLUT3 neurons represent an attractive cellular target for treating allodynia originated from both cutaneous and rectal tissues.…”
Visceral pain is among the most prevalent and bothersome forms of chronic pain, but their transmission in the spinal cord is still poorly understood. Here we used a focal colorectal distention (fCRD) method to drive visceromotor responses (VMRs) plus affective pain-indicative aversive learning. We first found that spinal CCK neurons were necessary for noxious fCRD to drive both VMRs and aversion. We next showed that spinal VGLUT3 neurons mediate affective visceral allodynia, whose ablation caused loss of aversion evoked by low-intensity fCRD in mice with gastrointestinal (GI) inflammation or spinal circuit disinhibition. Importantly, these neurons are dispensable for driving VMRs. Anatomically, VGLUT3 neurons send projection to the parabrachial nuclei, whose photoactivation sufficiently generated aversion in mice with GI inflammation. Our studies suggest the presence of different spinal substrates that transmit nociceptive versus affective dimensions of visceral sensory information.
“…One hallmark for inflammatory visceral pain manifestation is the development of referred cutaneous mechanical hypersensitivity (Bai et al, 2019; Bielefeldt et al, 2006; Bourdu et al, 2005; Cao et al, 2021; Gao et al, 2021; Jain et al, 2022; Laird et al, 2000; Laird et al, 2002; Lv et al, 2019; Traub et al, 2008; Zhou et al, 2008). Such referred hypersensitivity was also abolished in VGLUT3 Lbx1 -Abl mice, suggesting that VGLUT3 neurons must be part of previously proposed spinal circuits receiving convergent inputs from cutaneous and visceral afferents (Cervero, 2009; Cui et al, 2022; Fang et al, 2021; Fuentes and Christianson, 2018; Gebhart and Bielefeldt, 2016; Luz et al, 2015; Qiao and Tiwari, 2020). Thus, spinal VGLUT3 neurons represent an attractive cellular target for treating allodynia originated from both cutaneous and rectal tissues.…”
Visceral pain is among the most prevalent and bothersome forms of chronic pain, but their transmission in the spinal cord is still poorly understood. Here we used a focal colorectal distention (fCRD) method to drive visceromotor responses (VMRs) plus affective pain-indicative aversive learning. We first found that spinal CCK neurons were necessary for noxious fCRD to drive both VMRs and aversion. We next showed that spinal VGLUT3 neurons mediate affective visceral allodynia, whose ablation caused loss of aversion evoked by low-intensity fCRD in mice with gastrointestinal (GI) inflammation or spinal circuit disinhibition. Importantly, these neurons are dispensable for driving VMRs. Anatomically, VGLUT3 neurons send projection to the parabrachial nuclei, whose photoactivation sufficiently generated aversion in mice with GI inflammation. Our studies suggest the presence of different spinal substrates that transmit nociceptive versus affective dimensions of visceral sensory information.
“…Recently, some DRG neurons have been reported to innervate both the skin and the distal colon simultaneously ( Fang et al, 2020 ). In vivo extracellular electrophysiological recordings of those DRG neurons revealed that they robustly respond to both expansions of the distal colon and the mechanical, nociceptive, warm, or cold stimulation of the cutaneous receptive field ( Fang et al, 2020 ). These results indicate that DRG neurons shared by both the skin and the distal colon participate in the transmission or modulation of multiple sensation signals.…”
When the body is under pathological stress (injury or disease), the status of associated acupoints changes, including decreased pain threshold. Such changes in acupoint from a “silent” to an “active” state are considered “acupoint sensitization,” which has become an important indicator of acupoint selection. However, the mechanism of acupoint sensitization remains unclear. In this study, by retrograde tracing, morphological, chemogenetic, and behavioral methods, we found there are some dorsal root ganglion (DRG) neurons innervating the ST36 acupoint and ipsilateral hind paw (IHP) plantar simultaneously. Inhibition of these shared neurons induced analgesia in the complete Freund’s adjuvant (CFA) pain model and obstruction of nociceptive sensation in normal mice, and elevated the mechanical pain threshold (MPT) of ST36 acupoint in the CFA model. Excitation of shared neurons induced pain and declined the MPT of ST36 acupoint. Furthermore, most of the shared DRG neurons express TRPV1, a marker of nociceptive neurons. These results indicate that the shared nociceptive DRG neurons participate in ST36 acupoint sensitization in CFA-induced chronic pain. This raised a neural mechanism of acupoint sensitization at the level of primary sensory transmission.
“…Fang in 2021 showed that inflammatory bowel diseases can cause hypersensitivity in a corresponding dermatome. 31 According to his study, this phenomenon reflects the fact that there is common innervation of the skin and visceral organs coming from the bifurcation of the C-nociceptive neurons ( Figure 5 ). Figure 5 Interrelation between visceral and cutaneous nociceptive neurons.…”
Section: Tissue Specific Variations Of Nociceptorsmentioning
The human body is constantly under the influence of numerous pathological factors: both external and internal. These factors can be potentially harmful and are perceived as such with a specialized nervous system subunit: the nociceptive system. The functional unit of the nociceptive system is the nociceptor. Recent studies have shown that nociceptors play a crucial role in maintaining of defensive homeostasis (responsive, immune, behavioral). Nociceptors respond to potentially harmful stimuli within viscera, bones, muscles, skin and specialized sensory organs. They function as complex predictors of harm through formation of pain stimulus. Their function and structures vary within different tissues. This variability reflects the anatomical and pathological peculiarities of varying tissues. Nociceptors play a significant role in adaptive, protective and behavioral reactions. Their functional capabilities and vast spread throughout the body make them the main units of the body’s defense system, allowing us to interact with the inner and outer environments.
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