Abstract
Peripheral nociceptors and their synaptic partners utilize neuropeptides for signal transmission. Such communication tunes the excitatory and inhibitory function of nociceptor-based circuits, eventually contributing to pain modulation. Corticotropin-releasing hormone (CRH) is the initiator hormone for the conventional hypothalamic-pituitary-adrenal axis, preparing our body for stress insults. Although knowledge of the expression and functional profiles of CRH and its receptors and the outcomes of their interactions has been actively accumulating for many brain regions, those for nociceptors are still under gradual investigation. Currently, based on the evidence of their expressions in nociceptors and their neighboring components, several hypotheses for possible pain modulations are emerging. Here we overview the historical attention to CRH and its receptors on the peripheral nociception and the recent increases in information regarding their roles in tuning pain signals. We also briefly contemplate the possibility that the stress-response paradigm can be locally intrapolated into intercellular communication that is driven by nociceptor neurons. Such endeavors may contribute to a more precise view of local peptidergic mechanisms of peripheral pain modulation.
Highlights
Pain and touch sensations occur through the relay of electrical impulses generated by somatosensory neural circuits, which comprise peripheral and central components [1]
Under spinal nerve injury (SNI)-neuropathic conditions, animals exhibited some changes in expression including robust increases in Corticotropin-releasing hormone (CRH) and transient receptor potential vanilloid subtype 1 (TRPV1) expression in contralateral small-diameter dorsal root ganglion (DRG) neurons and decreases in ipsilateral neurons. These differences again occurred in fiber staining in the corresponding spinal laminae: the contralateral side showed greater expression than the ipsilateral one. These results suggest that changes in CRH expression may be associated with
A comparative validation as an analgesic target is another way to interrogate neuropeptides and their receptors. Neuropeptides in nociceptors such as calcitonin-gene related peptide (CGRP), pituitary adenylate cyclase-activating peptide (PACAP), SP, vasoactive intestinal peptide (VIP), GAL, neuropeptide Y (NPY), VIP, SST, arginine vasopressin (AVP), and OXT all appear to play a crucial role in pain transmission
Summary
Pain and touch sensations occur through the relay of electrical impulses generated by somatosensory neural circuits, which comprise peripheral and central components [1]. Because pain exacerbation or attenuation often arises from such tuning, knowledge of their identities and tuning mechanisms at work may help to better understand the physiological aspect of pain, and to devise pain control strategies that target nociceptors [2] Local neuropeptides such as calcitonin-gene related peptide (CGRP) and a tachykinin substance. P (SP) are currently well known to be secreted by nociceptors and act as slow neurotransmitters, which lead us to experience tonic pain whereas the typical ones like glutamate and aspartate evoke sharp and fast pain when released synaptically Those local peptides may strengthen synapses in the spinal cord or medulla and may occasionally cause peripheral neurogenic inflammation. We overview the locations, roles, mechanisms, and hypotheses regarding how CRH and its receptors control pain transmission with up-to-date knowledge, focusing on the nociceptors
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