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As explained earlier, the basal fi ring rates of individual oxytocin neurons are
highly variable, but the responses of oxytocin neurons to IV kisspeptin were com-
pletely independent of basal fi ring rate. This observation, combined with the consis-
tent increase in fi ring rate evident in every oxytocin neuron challenged with IV
kisspeptin-10, makes it probable that, when circulating kisspeptin rises, every single
oxytocin neuron increases its fi ring rate. Hence, circulating kisspeptin is a potential
mechanism that could co-ordinate activity across the population of oxytocin neu-
rons; such co-ordinated oxytocin neuron activity is a pre-requisite for successful
milk ejection during lactation.
Vagal Mediation of Oxytocin Neuron Activation
by Peripheral Kisspeptin
As described earlier, information is relayed to the oxytocin neurons via various affer-
ent input pathways, including noradrenergic pathways from the brainstem that relay
vagal signals. This pathway is implicated in the co-ordination of neuroendocrine
changes occurring at birth and is well-established as completing the positive feedback
loop from the uterus to the oxytocin system in birth and lactation. Hence, we hypoth-
esised that circulating kisspeptin-10 might also converge on this pathway to act on the
SON, because Kiss1r are expressed in peripheral tissues, including the stomach and
small intestine [
1
], that are known to be innervated by the vagus nerve.
To test this hypothesis, we repeated our experiments after desensitisation of
vagal sensory fi bres using the sensory neurotoxin, capsaicin (8-methyl-
N
-vanillyl-
6-nonenamide). Capsaicin is a compound found in capsicums and hot chilli peppers
that creates a perception of burning in mammals via activation of the transient
receptor potential channel-vanilloid receptor subtype 1 (TRPV-1; capsaicin recep-
tor). While capsaicin initially excites thin primary afferent c-fi bres expressing
TRPV-1, when it is administered in large and/or repeated doses it results in the
desensitisation and defunctionalisation of the neurons [
63
]. TRPV-1 is expressed on
gastric primary vagal afferent fi bres [
64
], and capsaicin can act on these fi bres to
effectively block the vagal pathway into the brain with the advantage that efferent
vagal pathways are left intact.
We found that pre-treatment with intraperitoneal (IP) capsaicin completely elim-
inated the increase in fi ring rate of oxytocin neurons induced by IV kisspeptin-10,
as well as that induced by IV CCK (which is known to be mediated by vagal inputs
to the NTS [
47
]). Thus, it appears that in non-pregnant rats, IV kisspeptin-10 does
not directly excite oxytocin neurons, but acts as a hormone on peripheral targets
with projections to the SON relayed by vagal afferent fi bres. While we do not yet
have direct evidence to support the involvement of the NTS, or of noradrenergic
neurons, it is likely that NTS relays the vagal input to the SON through noradrener-
gic input. Of course, further work is still required to fully establish the pathway
from the vagus to the SON, which will involve retrograde-labelling from the SON
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