7: Modulatory Effects of Nitric Oxide on TRPV1 Induced Nociception in Rats

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Animal imaging (includes Ca2+ imaging, fluorescence microscopy), Behavioral studies

Background and Aims: TRPV1 receptors are predominantly expressed in primary sensory neurons whose cell bodies are located in the dorsal root ganglia (DRG), where they play a pivotal role in nociceptive signaling [1]. Nitric oxide (NO) is a diffusible signaling molecule that modulates pain processing, with context-dependent pro- or antinociceptive effects. However, the extent to which NO directly regulates TRPV1 receptor activity in primary nociceptors remains to be elucidated [2]. The present study aimed to investigate the effects of nitric oxide inhibition on TRPV1 activity in primary DRG cultures and to determine the impact of NO modulation on capsaicin-induced nociception in rats.

Methods: Primary DRG cultures from Wistar rats (n = 6) were prepared as previously described [3]. Nitric oxide inhibition and its effects on TRPV1 receptor activation were assessed using the non selective NOS blocker L-NAME (100 µM). Membrane depolarization was measured by confocal microscopy using the voltage-sensitive dye DiBAC4(3). For in vivo experiments, the nociceptive behavior induced by capsaicin intraplantar injection (10 µg/50 µL) in Wistar rats was recorded for 5 min (n = 10 per group). Saline or L-NAME was administered by the intraperitoneal, intrathecal, or intraganglionic routes 15 min before capsaicin injection, or by intraplantar co-administration with capsaicin.

Results: In cultured cells, administration of the TRPV1 agonist capsaicin resulted in a membrane depolarization (−0.37 ± 0.03) that was increased in the presence of the NOS inhibitor (0.60 ± 0.06). Behavioral experiments in rats showed that intraperitoneal administration of L-NAME enhanced capsaicin-induced nociceptive responses compared with controls (64.1 ± 5.3 vs. 40.6 ± 4.7), whereas intraplantar administration attenuated nociceptive responses (49.8 ± 2.0 vs. 82.7 ± 4.1). Spinal delivery also increased nociceptive responses compared with controls (50.7 ± 2.8 vs. 36.2 ± 3.5), while DRG injection had no effect.

Conclusions: NO exerts compartment-specific modulation of TRPV1-mediated nociception. Pharmacological NOS inhibition suggests that endogenous NO tonically regulates TRPV1 activity in primary sensory neurons, while its in vivo effects depend on the anatomical site of intervention. Spinal cord NOS inhibition may enhance nociception by impairing NO-dependent control of excitatory transmission in the dorsal horn, thereby facilitating central sensitization. In contrast, peripheral inhibition attenuates pain responses through local modulation of TRPV1 signaling. Together, these findings highlight the anatomical complexity of NO signaling along the nociceptive pathway and warrant further mechanistic investigation.

References: [1] Caterina, M. J., & Julius, D. (2001). The vanilloid receptor: a molecular gateway to the pain pathway. Annual review of neuroscience, 24, 487–517. https://doi.org/10.1146/annurev.neuro.24.1.487
[2] Cury, Y., Picolo, G., Gutierrez, V. P., & Ferreira, S. H. (2011). Pain and analgesia: The dual effect of nitric oxide in the nociceptive system. Nitric oxide : biology and chemistry, 25(3), 243–254. https://doi.org/10.1016/j.niox.2011.06.004
[3] Linhart O, Obreja O, Kress M. The inflammatory mediators serotonin, prostaglandin E2 and bradykinin evoke calcium influx in rat sensory neurons. Neuroscience. 2003;118(1):69-74. doi:10.1016/s0306-4522(02)0096

Presenting Author: Alexia Oliveira Bispo dos Santos
Submitting Author: Alexia Oliveira Bispo dos Santos

Senior Author: Celina Monteiro da Cruz Lotufo

IASP 2026 Global Year theme of Neuropathic Pain: No

• Juliana Juliate Damacena Fernandes: Master's degree - Federal University of Uberlandia
• Taís de Campos Lima: Doctorate (PhD) - Federal University of Uberlandia
• Celina Monteiro da Cruz Lotufo: Doctorate (PhD) - Federal University of Uberlandia