A121 SILENCING ENTERIC SENSORY NEURONS ABOLISHES THE EXCITATORY EFFECT OF SERTRALINE ON VAGAL AFFERENTS Journal Articles uri icon

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abstract

  • Abstract Background Two thirds of vagal afferents supplying the small intestine terminate on intrinsic primary afferent neurons (IPANs) of the enteric nervous system via intraganglionic laminar endings (IGLEs) rather than the luminal epithelium (FASEB J, 28, 3064–3074, 2014). The IPAN to IGLE connection forms a functional intramural sensory synapse within the myenteric plexus. We have recently shown (Sci Rep, 9, 14290, 2019) that the antidepressant behavioural effects of selective serotonin reuptake inhibitors (SSRIs) are dependent on the vagus nerve and that intraluminal application of the SSRIs fluoxetine and sertraline increase vagal afferent firing rate in vitro. Aims We hypothesize that the vagal afferent response to intraluminal sertraline is mediated by IPAN to IGLE sensory signaling. Methods Mesenteric nerve recordings were performed using 2–3 cm jejunal segments and attached mesentery from 6–8 weeks old male Balb/c mice. Jejunal tissue was pinned out and dissected in a petri dish of Krebs to remove excess mesentery to isolate the mesenteric nerve bundle. Multi-unit electrical activity was recorded by patch-clamp electrode using an amplifier and signal converter by sucking onto the mesenteric nerve bundle with a glass micropipette. Baseline firing was recorded for 30 mins during luminal Krebs perfusion. The vagal afferent firing response to sertraline (10 µM) was measured in the absence or presence of 5 µM of the intermediate conductance calcium-dependent (IKCa) channel opener 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazole-2-one (DCEBIO) to the serosa to selectively silence IPANs. Dataview software (J Neuroscience Methods, 185, 151, 2009) was used to isolate single unit firing post-hoc. Vagal fibre action potentials were identified by response to CCK. Results Intraluminal sertraline decreased the mean vagal interspike interval (increased vagal firing frequency) by 29% (p = 0.008) compared to Krebs control (N = 15 fibres). In contrast, addition of luminal sertraline in the presence of DCEBIO increased mean vagal interspike interval by 48% (p = 0.0103) compared to Krebs control (N = 12 fibres). Serosal addition of the N-type Ca2+ channel blocker w-Conotoxin GVIA simultaneously with luminal sertraline increased the mean vagal interspike interval by 12% (p = 0.0282) compared to Krebs control (N = 7 fibres). Conclusions Silencing of myenteric IPANs to vagus neurotransmission blocked excitatory response of vagal afferent fibres to intraluminal sertraline. Blocking myenteric neurotransmission reduced the vagus excitatory response to sertraline by more than 50%. These results suggest that the therapeutically necessary vagus nerve stimulation by sertraline involves activation of the myenteric intramural sensory synapse. Funding Agencies NSERC, OGS

publication date

  • February 26, 2020