Anales de la RANM

14 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 S U P L E M E N T O I SIMPOSIO · JÓVENES INVESTIGADORES Libro de Abstracts An RANM. 2021;138(03).supl01: 14 - 54 sigma-1 disminuye la sensibilización periférica mediante el incremento del tono opioide endógeno en las neuronas C peptidérgicas, que producen END2, mientras que no altera la sensibilización de los nociceptores C no peptidérgicos. Nuestros hallazgos se resumen en la Figura 1. Agradecimientos: Agencia Estatal de Investi- gación (10.13039/501100011033 - SAF2016- 80540R y FPU16/03213), Universidad de Granada (PPJIB2019.11), Junta de Andalucía (grupo CTS 109) y fondos FEDER. The algogenic chemicals produced during patholog- ical pain sensitize peripheral sensory neurons, favoring the development of hyperalgesia. While prostaglandin E2 (PGE2) and nerve growth factor (NGF) sensitize peptidergic C-nocicep- tors (TRPV1+), glial-derived neurotrophic factor (GDNF) sensitizes non-peptidergic C (IB4+) neurons. The sigma-1 receptor is a Ca 2+ -sensitive chaperone present in peripheral sensory neurons, which binds to TRPV1 and µ-opioid receptors (MOR). However, the functional impact of these interactions is unknown. In our present research, we show that the administration of the sigma-1 antagonists S1RA and BD-1063, in mice, reversed mechanical hyperalgesia induced by PGE2 and NGF, but not mechanical hypersensitivity induced by GDNF. The antihyperalgesic effect induced by sigma-1 antagonism was abolished by the sigma-1 agonist PRE-084, as well as by both the periph- eral opioid antagonist naloxone methiodide and the selective MOR antagonist cyprodime, but not by the κ antagonist nor-binaltorpimine or by the δ antagonist naltrindole. These results indicate that the antihyperalgesic effect of sigma-1 antagonists is mediated by peripheral MOR activation. Using immunohistochemical assays, we determined the presence of the endogenous MOR agonist endomorphin-2 (END2) in TRPV1+ nociceptors, but not in IB4+ nociceptors. Using resiniferatoxin, a molecular scalpel, we selectively ablated both TRPV1+ neurons and END2 labeling, confirming the presence of this opioid peptide on peptidergic C-nociceptors. The administration of an antibody against END2 in the sensitized paw reversed the antihyperalgesic effect induced by sigma-1 antago- nists, indicating that the action of this endoge- nous opioid peptide is essential for the antihy- peralgesic effect of sigma-1 antagonists. Using recombinant proteins, we show that the sigma-1 antagonist S1RA dissociates the sigma-1 receptor from the C-terminus of TRPV1 and increases its binding to the C-terminus of MOR. In other words, sigma-1 antagonism moves sigma-1 receptors from TRPV1 to MOR as part of its mechanism for opioid modulation. Therefore, the sigma-1 receptor could participate in the communication between TRPV1 and MOR. We show that PGE2 increased calcium flux induced by capsaicin, the prototype TRPV1 agonist, in cultured dorsal root ganglia neurons (DRGs). This increase in calcium flux was reversed by S1RA, and in a naloxone-sensitive manner. These results are consistent with the in vivo effects induced by sigma-1 antagonism, which are dependent on opioid activation. In summary, our results suggest that sigma-1 antagonism decreases peripheral sensitization by the increase of the endogenous opioid tone in peptidergic C-neurons, which produce END2, while it does not alter sensitization of non-peptidergic C-nocicep- tors. Our findings are summarized in Figure 1. Acknowledgments: Spanish State Research Agency (10.13039 / 501100011033 - SAF2016- 80540R and FPU16 / 03213), University of Granada (PPJIB2019.11), Junta de Andalucía (CTS 109 group) and ERDF funds. Figure 1. Hypothesis of the mechanism of action of sigma-1 receptor antagonism in the hyperalgesia induced by peptidergic C-neuron sensitization.