The Role of Corticotropin-Releasing Hormone at Peripheral Nociceptors: Implications for Pain Modulation

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.

Keywords: corticotropin-releasing hormone; corticotropin-releasing hormone receptor; dorsal root ganglion; nociceptor; pain.

Figure 1

A conceptual diagram depicting the role of CRH and its receptors in the peripheral nociceptor-based circuit. Injured or inflamed intestines may locally secrete CRH, stimulating CRHRs in the peripheral termini of nociceptors, which can promote their excitations via Gs- or Gq-protein α subunits-mediated intracellular signaling. By contrast, CRH antidromically released from those termini can occasionally activate CRHRs in infiltrated immune cells, dampening nociceptor signals by providing endogenous opioids. CRH released from the central termini of nociceptors may possibly activate interneuronal CRHRs in the superficial laminae in the spinal cord and then pain transmission can be attenuated. Spinal deep laminae are also known to express CRHRs but the cellular components that stimulate those by secreting ligands remains to be determined.