Neuropharmacology 2001 Jul;41(1):130-7
Intra-amygdala injection of the substance P (NK(1) receptor) antagonist
L-760735 inhibits neonatal vocalisations in guinea-pigs.
Boyce S, Smith D, Carlson E, Hewson L, Rigby M, O'Donnell R, Harrison T, Rupniak
NM.
Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings
Park, Eastwick Road, Essex CM20 2QR, Harlow, UK
The involvement of the basolateral amygdala in mediating the inhibition of neonatal vocalisation by
substance P (NK(1) receptor) antagonists was examined. These studies determined whether the
time course for separation-induced vocalisations in guinea-pig pups coincided with NK(1)
receptor internalisation (a marker of substance P release) in the amygdala, and whether
vocalisations could be blocked by focal injection of the NK(1) receptor antagonist L-760735
into this brain region. The peak period for neonatal vocalisations occurred 5-10 min following
maternal separation. This coincided with the peak increase in the number of cells in the
basolateral amygdala exhibiting NK(1) receptor endocytosis, consistent with the proposal that
substance P is released in the amygdala as a result of isolation stress. Focal injection of
L-760735 (15 nmol per side) but not L-770765 (an analogue of L-760735 which has low
NK(1) receptor affinity) into the basolateral amygdala attenuated separation-induced
vocalisations. In contrast, injection of L-760735 (15 nmol per side) into the dorsal ventricular
nucleus of the thalamus, a region with relatively low density of NK(1) receptors, had no effect on
neonatal vocalisations. These findings are consistent with other evidence that the amygdala is one
possible site of action for the inhibition of neonatal vocalisations by substance P antagonists.
Eur J Neurosci 2001 Jun;13(11):2099-104
Colocalization of CGRP with 5-HT1B/1D receptors and substance P in
trigeminal ganglion neurons in rats.
Ma QP, Hill R, Sirinathsinghji D.
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, Neuroscience
Research Centre, Terlings Park, Harlow CM20 2QR, UK.
Vasodilatation in the dura mater has been implicated in migraine pathogenesis. Anti-migraine
triptan drugs block vasodilatation by binding to 5-HT1B/1D receptors localized on the peripheral
sensory terminals and dural blood vessel smooth muscles. Previous studies suggest that calcitonin
gene-related peptide (CGRP) released from Adelta-fibres plays a more important role than
substance P (SP) released from C-fibres in inducing dural vasodilatation and that one of the
antimigraine mechanisms of triptan drugs is inhibiting CGRP release. In the present study, the
relationship between CGRP and 5-HT1B/1D receptors, and between CGRP and SP in the
trigeminal ganglion neurons in rats was examined by double immunohistochemical staining.
CGRP, 5-HT1B, 5-HT1D and SP-positive trigeminal ganglion neurons were all predominantly
small and medium-sized. In the trigeminal ganglia, approximately 50% of CGRP-positive neurons
were 5-HT1B positive. Similarly, approximately 55% of CGRP-positive neurons were 5-HT1D
immunoreactive. Approximately 50% of CGRP-positive neurons were SP-positive, while 93% of
SP-positive neurons were CGRP-positive, suggesting that nearly all SP-positive neurons also
contain CGRP. The fibre types of the 5-HT1B- and 5-HT1D-positive neurons were further
investigated with an antibody against the A-fibre marker 200-kDa neurofilaments (NF200).
Approximately 46% of the 5-HT1B-positive and 43% of the 5-HT1D-positive trigeminal
ganglion neurons were also NF200 positive, indicating that many A-fibre trigeminal neurons
express 5-HT1B or 5-HT1D receptors. These results support the hypothesis that one important
action of antimigraine drugs is the inhibition of CGRP release and that Adelta-fibres may play an
important role in migraine pathogenesis.
Trends Pharmacol Sci 1999 Dec;20(12):485-90
Discovery of the antidepressant and anti-emetic efficacy of substance P
receptor (NK1) antagonists.
Rupniak NM, Kramer MS.
Merck Sharp & Dohme Neuroscience Research Centre, Harlow, Essex, UK.
The development of small-molecule antagonists of the substance P (SP)-preferring tachykinin
NK1 receptor during the past decade represents an important opportunity to exploit these
molecules as novel therapeutic agents. On the basis of its anatomical localization and function, SP
has been implicated in diverse pathophysiologies; of these, diseases of the CNS have been
examined in the greatest detail. Although SP is best known as a pain neurotransmitter, it also
controls vomiting and various behavioural, neurochemical and cardiovascular responses to stress.
Recent clinical trials have confirmed the efficacy of NK1 receptor antagonists to alleviate
depression and emesis but, surprisingly, not pain. Thus, multiple clinical trials, targeted to
appropriate patient populations, are necessary to define the therapeutic potential of novel
neurotransmitter ligands.
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Etc.
I'll say this....... while not a big fan of pills, I use Merck's triptan, Maxalt. It has made a huge difference in the quality of my life. My headaches are gone within 30 minutes of taking it (100%, thus far, 10 of 10 in about four months). This is not a placebo effect...... it's a real difference, effective therapy for intractable headache, after 30 years of searching for a solution. |
