The role of amygdala calcitonin gene-related peptide receptors on the development of persistent bladder pain in mice
Source: Pain
Authors: Lakeisha A Lewter, Blesson K Paul, Arnold M Salazar, Uma R Chatterjee, Hoai Phuong T Pham, Myra Z Khan, Anna E Schmitz, Abraham M Nofal, Mursal M Hussein, Indira U Mysorekar, Benedict J Kolber, Publication Date: Thu, 19 Feb 2026 06:00:00 -0500
Pain. 2026 Jun 1;167(6):1440-1452. doi: 10.1097/j.pain.0000000000003939. Epub 2026 Feb 18.
ABSTRACT
Bladder pain significantly impacts millions worldwide, severely affecting their quality of life and posing a major clinical challenge. Understanding the mechanisms underlying persistent bladder pain is critical for developing better therapeutic strategies. In this study, we investigate the effects of cyclophosphamide (CYP)-induced persistent bladder sensitization to explore the lateralized contribution of amygdala calcitonin gene-related peptide receptors (CGRP-Rs) on pain-like changes in mice. We demonstrate that CYP induces hypersensitivity lasting up to 14 days postinjury (DPI) in the urinary bladder distention assay and up to 21 DPI when assessing abdominal mechanical sensitivity. Despite persistent pain-like changes, no significant bladder histological changes were observed. Based on previous findings that CGRP signaling from the parabrachial nucleus contributes to central amygdala (CeA) lateralization, we hypothesized that CGRP-Rs play a key role in driving visceral bladder pain-related hemispherical differences. We show that inhibiting CGRP-R activity with the antagonist CGRP 8-37, in the right CeA attenuates bladder pain-like behavior, whereas left CeA inhibition sustains CYP-induced hypersensitivity. Electrophysiological recordings revealed increased firing frequency in CGRP-R-positive cells in the right CeA 7 DPI. In vivo single photon calcium imaging demonstrated increased Ca transients in CGRP-R-positive cells in the right CeA, upon the presentation of a stimulus at 0 DPI and overall at 2 DPI, further confirming the pronociceptive role of CGRP-Rs in the right CeA. Taken together, these findings provide a crucial foundation for understanding pain-induced CeA lateralization and for further studies identifying how targeting CGRP signaling could provide bladder pain relief.
PMID:41711181 | DOI:10.1097/j.pain.0000000000003939
Pubmed ID: pubmed:41711181
Identifiers: pmid:41711181, doi:10.1097/j.pain.0000000000003939,
Paper chosen by Rajesh Khanna
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Bladder pain is a common, poorly treated condition, and the central mechanisms that sustain it remain unclear. Using a cyclophosphamide (CYP) model of persistent bladder sensitization in mice, Lewter and colleagues show that CYP produces hypersensitivity lasting up to 14 days (bladder distention) and 21 days (abdominal mechanical sensitivity) without detectable bladder tissue damage—indicating a central rather than peripheral driver. The authors traced this to lateralized CGRP receptor (CGRP-R) signaling in the central amygdala (CeA): blocking CGRP-Rs in the right CeA with CGRP 8-37 relieved pain-like behavior, while left CeA blockade did not. Electrophysiology and in vivo calcium imaging confirmed heightened activity in right-CeA CGRP-R–positive neurons after injury, establishing these cells as pronociceptive drivers of persistent visceral pain.
What makes this paper exciting: it is the first demonstration that bladder pain is driven by a right-lateralized CGRP circuit in the central amygdala, reframing a peripheral disorder as a central, side-specific one and pointing to amygdalar CGRP signaling as a precise, non-opioid target for chronic bladder pain.