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cetylcholine receptor, nicotinic (nAChR) [GE]
Mice generated lacking the alpha4 subunit
and beta2 subunit of the nicotinic acetylcholine receptor. The
response to painful stimuli was not any different in wild-type
mice, mice lacking the alpha4 subunit, or mice lacking the beta2
subunit. However, the antinociceptive response to nicotine was
reduced in both knockout strains. Results suggest that the alpha4
and beta2 subunits are components of the nicotinic pain pathways.
Marubio et al., Nature, 398:805-810, 1999.
ß-arrestin-2 [GE]
G-protein coupled heptahelical receptors (GPCR)
are regulated by GPCR kinases (GRKs) which phosphorylate activated
receptors and promote their interaction with ß-arrestins. The
downstream interaction of arrestins with the phosphorylated GPCR
receptor inhibits further between GPCR and guanine nucleotide
binding proteins (G-proteins), dampening the signalling cascade
associated with receptor activation. This eventually leads
to GPCR desensitization. Knock-out mice deficient in ß-arrestin-2
(ßarr2-KO or ßarr2 -/-) were produced by homologous
recombination. ßarr2-KO mice displayed enhanced and
prolonged morphine-induced antinocieception when compared to wild-type
mice. The response of mice to a hot-plate stimulus (56ºC)
was determined before and after morphine administration. Knock-out
mice showed a significant potentiation of morphine-induced analgesia,
exhibiting analgesia for up to four hours after a single dose of
morphine while, in control mice, the effects wore off after only
90 minutes. Morphine-induced analgesia is mediated by the
mu-opioid receptor. It is suggested that the deficiency in ß-arrestin-2
improves the tolerance to pain in the presence of morphine by impairing
receptor desensitization. Bohn et al., Science, 286:2495-2498,
24 Dec. 1999. ßarr2-KO mice, in contrast to wild-type
mice, failed to become tolerant or less responsive to the antipain
properties of morphine after both acute and chronic administration. Biochemical
studies showed that desensitization of the mu-opiate receptor occurred
in wild-type mice, but not in ßarr2-KO mice, indicating that
desensitization of the mu-opiate receptor contributes to morphine
tolerance. Bohn et al., Nature, 408:720-723, 7 Dec. 2000.
See, Entry under Craving, Opiate, for ß-arrestin-2.
neuropeptide Y1 receptor [GE]
Neuropeptide Y ("NPY") has antinociceptive
activity, apparently by inhibiting the release of substance P and
other "pain neurotransmitters" in the spinal cord dorsal
horn. Mice deficient in the neuropeptide Y1 receptor were
created by homologous recombination. These mice showed increased
sensitivity to thermal, chemical, and mechanical pain. The
results suggest that Y1 ligand may mediate antinociception. Naveilhan
et al., Nature, 409:513-517, 25 Jan. 2001.
preprotachykinin (PPY-A); neurokinin A (NKA); substance P [GE]
Transgenic "knock-out" mice were produced
for the PPY-A gene which codes for NKA and substance P. Response
to mildly painful stimuli was intact and similar to wild-type mice
but the response to moderate to intense stimuli was significantly
reduced. Results suggest that tachykinins cause release of tachykinins
which are critical neurotransmitters for moderate and intense pain
messages. Cao et al., Nature, 392: 390-394, 1998; Zimmer et al,
Proc. Natl. Acad. Sci., 95:2630-2635, 1998.
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