125: Anterior Cingulate Cortex Mu-Opioid Receptor-expressing Neurons Regulate Chronic Visceral Pain

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic primary visceral / pelvic pain, , , , , Neurocircuit modulation (could include opto, DREADDs), , , ,

Background and Aims: Chronic visceral pain is a common clinical problem with complex underlying mechanisms. The anterior cingulate cortex (ACC) plays a critical role in pain processing[1]. The μ-opioid receptor (MOR) is abundantly expressed in the ACC[2] and both exogenous and endogenous opioids have been reported to modulate pain processing in the ACC[3-4], however, the function of MOR–expressing neurons within the ACC remains unclear. This study aims to investigate the role of MOR-expressing neurons in layer V of the ACC in visceral pain.

Methods: We investigated the role of MOR-expressing neurons in layer V of the ACC in visceral pain using a chemogenetic approach. MOR-Cre rats received stereotaxic injections of AAV2-hSyn-DIO-hM3D/hM4D-mCherry into layer V of the ACC to selectively activate or inhibit MOR-expressing neurons, respectively. Two weeks later, visceral pain was induced by colorectal administration of TNBS, a well-established model of colitis, and pain behaviors were assessed using electromyographic (EMG) recordings of visceromotor response (VMR) to colorectal distension (CRD) at baseline and day 7 after TNBS treatment. After the EMG testing, all rats were perfused and brain tissues were collected for further analysis.

Results: We found that TNBS-induced colitis significantly increased VMR to CRD on day 7 compared with baseline, reflecting enhanced visceral pain. Chemogenetic activation of ACC MOR-expressing neurons by hM3D significantly reduced VMR to CRD on day 7 after TNBS treatment. Conversely, inhibition of ACC MOR-expressing neurons by hM4D markedly increased VMR to CRD on day 7.

Conclusions: These findings suggest that ACC MOR-expressing neurons play a modulatory role in pain-related neural circuits during chronic visceral pain.

References: [1] Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology. 1997 Jan;112(1):64-72.
[2] Zamfir M, Sharif B, Locke S, et al. Distinct and sex-specific expression of mu opioid receptors in anterior cingulate and somatosensory S1 cortical areas. Pain. 2023;164(4):703-716.
[3] McDevitt DS, McKendrick G, Graziane NM. Anterior cingulate cortex is necessary for spontaneous opioid withdrawal and withdrawal-induced hyperalgesia in male mice. Neuropsychopharmacology. 2021 Oct;46(11):1990-1999.
[4] Navratilova E, Xie JY, Meske D, Qu C, Morimura K, Okun A, Arakawa N, Ossipov M, Fields HL, Porreca F. Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain. J Neurosci. 2015 May 6;35(18):7264-71.

Presenting Author: Linqian Yu
Submitting Author: LINQIAN YU

Senior Author: Yi Dai

IASP 2026 Global Year theme of Neuropathic Pain: No

• Shaoqi Duan: PhD - Hyogo Medical University
• Yilong Cui: PhD - Hyogo Medical University
• Yumi Tsutsumi: PhD - Hyogo Medical University
• Koichi Noguchi: PhD - Hyogo Medical University
• Yi Dai: PhD - Hyogo Medical University