Opioids + Addicktion Flashcards
DICK
Mental and substance abuse the leading cause of years lived with disability in a review of global data
Whiteford et al., 2010
Action of Gi/o
Inhibit adenyl cyclase (inhibits CAMP) and inhibit VSCCs and activate VSPCs
Downstream effects of barr2 recruitment
on SRC and AKT
Inhibition of Barr2 results in left shift of morphine dose response curve
Yang et al., 2011
Studies have shown that Barr2 knockout attenuates tolerance to morphine and improves its analgesic effects
Yang et al., 2011
How do opioids increase DA release
Hyperpolarise inhibitory GABA neuron – disinhibited DAergic neuron
Since opioid system is involved in reward, dysregulation may cause…
abberant behaviours such as binge eating and gambling
MOP antagonist reduces hedonic response to certain sweetened food and decreases calorific intake - opioid antagonists in binge eating disorderr?
Ziauddeen et al., 2014
Also evidence for MOP antag in gambling and drug addictions
Rosenberg et al., 2013, Giuliano et al., 2013
Abolishing MOPs prevents the analgesic and conditioned place preference response in mice - reduced reward??
Matthes et al., 1996
absence of Barr2 reduces morphine tolerance
Bohn et al., 1999
How might Barr2 cause tolerance
Endocytosis
Prolonged morphine administration causes constitutively active MOP activity
Wang et al., 2004
Increased constituvive activity causes enhanced naloxone induced aversion
Shoblock and Maidment 2006
The basal analgesic displayed by Baar2-lacking mice is mediated by constitutive MOP activity - how do we know and who said this?
Lam et al., 2011
Effects are blocked by inverse agonist naloxone but not neutral antagonist
Barr2 lacking mice still show dependence but this is NOT through constitutively active MOPs as knockouts do not show enhanced place aversion with naloxone compared wth WTs
Lam et al., 2011
Barr2 knockouts show decreased side effects including constipation, locomotion, respiratory depression
Urs et al., 2011, Raehal et al., 2005
Morphine induced MOP activaton produces locomotion which is attenuated in Barr2 but not Barr1 knockouts
Urs et al., 2011
TH-/- mice lack morphine indued locomotion. This is restored by ldopa injection
Hnasko et al., 2005
TH-/- mice exhibit mrphine induced conditioned place preference
Hnasko et al., 2005
Morphine induced locomotion is attenuated in Barr2 (but not Barr1) knockouts. Knockout of D1 and D2 Rs also attenuate locomotion. So locomotor response of morphine is dependent on D1Rs,D2Rs and barr2
Urs et al., 2011
Barr2 has downstream effects on ERK pathway in which MEK is involved. MEK inhibitor attenuates locomotor response so this is probs how barr2 mediates locmotion
Urs et al., 2011
