K Opiods For Pain Bup
K Opiods For Pain Bup
K Opiods For Pain Bup
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ACKNOWLEDGEMENTS
This work was supported by the
Klarman Family Foundation and NIDDK
(DK073311) research grants to MR.
Maribel Rios1
1
Deparment of Neuroscience, Tufts University School
of Medicine, Boston, MA, USA
E-mail: [email protected]
DISCLOSURE
The author declares that during the past 3 years, she
has been compensated for offering scientific opinions
to Wyeth Pharmaceuticals. This does not reflect a
conflict of interest with respect to this article.
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Neuropsychopharmacology Reviews (2011) 36, 368369;
doi:10.1038/npp.2010.139
The Therapeutic
Potential of k-Opioids
for Treatment of Pain
and Addiction
When the k-subtype of opioid receptor
was first distinguished, there was tremendous interest in developing analgesics that would provide pain-relief
without activating the reward pathways
stimulated by morphine-like m-opioids.
A nonaddictive opioid has been a holy
grail of medicinal chemistry ever since
Friedrich Serturner isolated morphine
from opium in 1804. Selective k-agonists were developed, but quickly found
to produce different problems including
dysphoria, diuresis, and constipation.
In addition, their maximal analgesic
effects were weaker than m-opioids in
rodents. But interest in k-opioids as
therapeutic tools did not completely
die; Shippenberg and colleagues found
that k-agonists reduced the rewarding
effects of co-administered addictive
drugs; k-opioid analgesia using pentazocine was seen as an alternative for
pain control in people with a risk of
drug abuse; and k-agonists entered
clinical trials for the treatment of pain
and itch (see Millan, 1990).
Although enthusiasm for agonists
waned, interest in k-antagonists as
therapeutic tools got a boost when
Carlezon and colleagues showed their
activity in the forced swim assay,
predictive of antidepressant activity
(Mague et al, 2003). Following on that
study, we reported that k-antagonism
blocked stress-induced potentiation
of cocaine reinforcement (McLaughlin
et al, 2003). Numerous studies have
replicated and extended those findings
showing the utility of k-antagonists
to block stress-induced reinstatement
of extinguished cocaine- and ethanolseeking, block m-opioid and cannabinoid withdrawal signs, and block
the aversive effects of nicotine. All
these effects of k-antagonists can be
attributed to block of the actions
of endogenous dynorphins, which are
k-selective opioid peptides released
during the stress response (Land et al,
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Neuropsychopharmacology
HOT TOPICS
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Ligand-directed signaling:
Full and partial KOR agonists
KOR
G
arrestin
G
GRK3
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Neuropsychopharmacology
DISCLOSURE
C Chavkin has no conflicts of interest or consulting
relationships to disclose, but has received outside
compensation for seminars on his NIH-funded research
during the past 3 years at: AstraZeneca, NIDA,
UC Irvine, Uniformed Services University, University of
Minnesota, Sepracor, Eli Lilly, Adolor, and Vanderbilt.
In addition, he has received outside compensation for
reviewing grants for CSR-NIH and NIDA.
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Bruchas MR, Chavkin C (2010). Kinase cascades and
ligand-directed signaling at the kappa opioid receptor. Psychopharmacology (Berl) 210: 137147.
Bruchas MR, Yang T, Schreiber S, Defino M, Kwan
SC, Li S et al (2007). Long-acting kappa opioid
antagonists disrupt receptor signaling and produce
noncompetitive effects by activating c-Jun Nterminal kinase. J Biol Chem 282: 2980329811.
Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ,
Chavkin C (2008). The dysphoric component of
stress is encoded by activation of the dynorphin
kappa-opioid system. J Neurosci 28: 407414.
Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz
HC, Zhang Y, Stevens Jr WC et al (2003).
Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats.
J Pharmacol Exp Ther 305: 323330.
McLaughlin JP, Marton-Popovici M, Chavkin C (2003).
Kappa opioid receptor antagonism and prodynorphin
gene disruption block stress-induced behavioral
responses. J Neurosci 23: 56745683.
Melief EJ, Miyatake M, Bruchas MR, Chavkin C
(2010). Ligand-directed c-Jun N-terminal kinase
activation disrupts opioid receptor signaling. Proc
Natl Acad Sci USA 107: 1160811613.
Millan MJ (1990). Kappa-opioid receptors and analgesia. Trends Pharmacol Sci 11: 7076.
Neuropsychopharmacology Reviews (2011) 36, 369370;
doi:10.1038/npp.2010.137
New Treatments in
Amyotrophic Lateral
Sclerosis
Identification of New ALS
Relevant Genes and Animal
Model Development
For the past 15 years, the field of
amyotrophic lateral sclerosis (ALS)
pathophysiology and drug development has largely been dominated by