TRPV₁ mediates the uterine capsaicin-induced NMDA NR2B-dependent cross-organ reflex sensitization in anesthetized rats

Abstract

Spinal cord-mediated cross-organ sensitization between the uterus and the lower urinary tract may underlie the high concurrence of obstetrical/gynecological inflammation and chronic pelvic pain syndrome characterized by urogenital pain. However, the neural pathway and the neurotransmitters involved are still unknown. We tested the hypothesis that the excitation of capsaicin-sensitive primary afferent fibers arising from the uterus through the stimulation of transient receptor potential vanilloid 1 (TRPV1) induces cross-organ sensitization on the pelvic-urethra reflex activity. Capsaicin (1-1,000 microM, 0.05 ml) was instilled into the uterus to induce cross-organ reflex sensitization. Activation of capsaicin-sensitive primary afferent fibers by capsaicin instillation into the uterine horn sensitized the pelvic-urethra reflex activity that was reversed by an intrauterine pretreatment with capsaizepine, a TRPV1-selective antagonist. Intrathecal injection of AP5, a glutamatergic N-methyl-D-aspartate (NMDA) antagonist, and Co-101244, an NMDA NR2B-selective antagonist, both abolished the cross-organ reflex sensitization caused by capsaicin instillation. These results demonstrated that TRPV1 plays a crucial role in contributing to the capsaicin-sensitive primary afferent fibers mediating the glutamatergic NMDA-dependent cross-organ sensitization between the uterus and the lower urinary tract when there is a tissue injury.

EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B

“…In the last decade, studies have demonstrated that the interactions between EphBRs and their ephrinB ligands modulate neural plasticity induction in the mammalian central nervous system, mainly, but not exclusively, via exhibiting effects on NMDAR (8,12). A recent study also demonstrated that, in association with thermal hyperalgesia, EphBR activation caused by immunoglobulin fusion protein of ephrinB2 (ephrinB2-Fc)-induced, Src kinase-dependent NR2B phosphorylation in the spinal cord (2), suggesting that ephrinB2-EphBR tyrosine kinase interactions could probably modulate pain signaling via spinal Src-dependent NMDAR phosphorylation (2).Although further proof is still needed for the physiological and/or pathophysiological relevance, the induction of pelvicurethra reflex potentiation (15, 16), a form of NR2B phosphorylation-dependent neural plasticity (5,25,31,41), has been linked to the development of visceral pain from pelvic organs (26,27,30,32,33). Studies have shown that the activation of nociceptive afferent fibers expressing transient receptor potential vanilloid/transient receptor potential ankyrin by the instillation of irritants into the uterus (32, 33) and the descending colon (29) facilitated pelvic-urethra reflex activity in a crossorgan manner.…”

“…Although further proof is still needed for the physiological and/or pathophysiological relevance, the induction of pelvicurethra reflex potentiation (15, 16), a form of NR2B phosphorylation-dependent neural plasticity (5,25,31,41), has been linked to the development of visceral pain from pelvic organs (26,27,30,32,33). Studies have shown that the activation of nociceptive afferent fibers expressing transient receptor potential vanilloid/transient receptor potential ankyrin by the instillation of irritants into the uterus (32, 33) and the descending colon (29) facilitated pelvic-urethra reflex activity in a crossorgan manner.…”

“…Studies have shown that the activation of nociceptive afferent fibers expressing transient receptor potential vanilloid/transient receptor potential ankyrin by the instillation of irritants into the uterus (32,33) and the descending colon (29) facilitated pelvic-urethra reflex activity in a crossorgan manner. Recently, we reported that acute colonic nociceptive stimulation sensitized pelvic-urethra reflex activity via the upregulation of endogenous ephrinB2 expression, which activates EphB1 and EphB2 receptors and leads to Src-family kinase-dependent NR2B phosphorylation in the lumbosacral spinal cord (26).…”

Acute anal stretch inhibits NMDA-dependent pelvic-urethra reflex potentiation via spinal GABAergic inhibition in anesthetized rats

“…Recent studies on pelvic-urethra reflex, using intact spinal cord preparations, have demonstrated a glutamatergic N-methyl-D-aspartate (NMDA)-dependent spinal reflex potentiation in which the activity of this reflex was dynamically potentiated by repetitive (29) and tetanic (30) afferent inputs. Because pathological potentiation in this reflex activity was suggested to underlie the hyperactive urethra (10, 11, 26 -28), the activity-dependent spinal reflex potentiation seems to be a novel animal model for studying urethra continent function (12,13,28,39,(41)(42)(43)(44).…”

The effect of spinal cord injury on vagal afferents.

“…Cross-sensitization between the bladder and other pelvic viscera is a clinical concern that makes diagnosing and treating the etiology difficult (Berkley, 2005, Baranowski et al, 2008, Theoharides et al, 2008, van de Merwe et al, 2008. In humans and in animals, the organs that seem to be most often involved in pelvic cross-sensitization besides bladder and colon, with respect to spinal afferents, appear to be the pelvic urethra and the uterus (Dmitrieva et al, 2001, Giamberardino et al, 2001, Dmitrieva and Berkley, 2002, Morrison et al, 2006, Peng et al, 2008a, Peng et al, 2008b, Peng et al, 2009). …”