Tachykinins as mediators of slow EPSPs in guinea‐pig gall‐bladder ganglia: involvement of neurokinin‐3 receptors.

Abstract

1. The effects of endogenous tachykinins and related peptides on intact guinea-pig gallbladder neurones were investigated with single-electrode voltage-and current-clamp recording techniques.2. Pressure ejection of substance P (100 #M) caused a long lasting membrane depolarization that was associated with a decrease in input resistance. In cells that were voltage-clamped to their resting membrane potential, substance P activated an inward current. 3. The reversal potentials of the substance P-induced depolarization and inward current were -0 mV. In a low-Na+ solution, the substance P-induced depolarization and inward current were reduced in amplitude. 4. Substance P increased the excitability of neurones, as evidenced by a greater anodal break activity and an increase in the number of action potentials generated during a depolarizing current pulse. 5. Substance P, neurokinin A (NKA) and neurokinin B (NKB) were applied by superfusion to determine the relative potencies of these tachykinins. NKB was the most potent, with an EC50 of 24 nm. The EC50 values for NKA and substance P were 47-8 and 281 nM, respectively. 6. The neurokinin-3 (NK-3) receptor agonist senktide depolarized neurones with an EC50 of 6-3 nm. Neither the NK-1 receptor agonist [Sar9,Met(02)11]-substance P nor the NK-2 receptor agonist [/3-Ala8]-NKA (4-10) caused a measurable depolarization.7. The NK-3 antagonist [Trp7,fi-Ala8]-NKA (4-10) inhibited the responsiveness of gallbladder neurones to substance P with a KB (dissociation constant of receptor antagonist) of 49 nM, and depressed both capsaicin-induced depolarizations and stimulus-evoked slow EPSPs. 8. These data indicate that tachykinins mediate slow EPSPs in guinea-pig gall-bladder ganglia by activating NK-3 receptors on gall-bladder neurones. It is proposed that in response to inflammation or high intraluminal pressure, tachykinins may be released within ganglia by sensory fibres and act directly on intrinsic neurones to facilitate ganglionic transmission.

Relationship between postsynaptic NK1 receptor distribution and nerve terminals innervating myenteric neurons in the guinea‐pig ileum

“…These data suggest that tachykinins might be transmitters at synapses in the ganglia. Consistent with this are pharmacological studies in which a block of NK 1 or NK 3 receptors has antagonised neuro-neuronal transmission in enteric ganglia (Mawe, 1995;Johnson et al, 1998;Frieling et al, 1999;Neunlist et al, 1999). At the light microscope level, NK 1 receptors appear to be evenly distributed over the surfaces of nerve cells.…”

“…Previous studies have shown that tachykinin-immunoreactive nerve terminals make appositions with the vast majority of myenteric neurons (Llewellyn-Smith et al, 1984). As many myenteric neurons express NK 3 receptors (Mawe, 1995;Johnson et al, 1998;Frieling et al, 1999;Jenkinson et al, 1999), the distribution of tachykinin-containing nerve terminals is likely to be correlated with the presence of NK 3 receptors, as well as NK 1 receptors, on postsynaptic neurons. It is also likely that tachykinin-containing nerve terminals also form appositions with neurons that express neither NK 1 or NK 3 receptors.…”

Characteristics of mucosally projecting myenteric neurones in the guinea‐pig proximal colon

“…The role of substance P as a mediator of the sEPSP has already been shown in the guinea-pig ileum (Katayama & North, 1978) and the NK_3 receptor agonist senktide has been shown to induce sEPSPlike responses in AH neurones (Bertrand & Galligan, 1995). In addition, in myenteric neurones of the duodenum, the stomach, and the gall blader NK_3 receptor agonists were more effective in inducing sEPSP like responses than SP or NK_1 receptor agonists (Hanani et al 1988;Schemann & Kayser, 1991;Mawe, 1995). The inability of the NK_3 antagonist SR 142801 to fully block sEPSPs may have different causes.…”

Activation of the nociceptin/orphanin FQ receptor reduces bronchoconstriction and microvascular leakage in a rabbit model of gastroesophageal reflux

“…However, as N/OFQ is a long (17 aa) peptide and contains several positively charge residues, it is likely that the nerve endings and/or nerve connections between the esophagus and airways in the autonomic ganglia (Myers & Undem, 1993;Myers et al, 1996), where anatomical studies have demonstrated the presence of axon collaterals from visceral afferent fibers (gastrointestinal tract, bladder, airways) (Coleridge et al, 1989;Mawe, 1995;Canning et al, 1996;Myers et al, 1996), represent the site of action of N/OFQ. Interestingly, Canning et al (1998) have reported in an in vitro preparation of guinea-pig trachea and esophagus with their respective nerves that capsaicin elicited a concentrationdependent relaxation of the trachea only when the adjacent esophagus was intact.…”