Opioids + Addicktion

Question 1

Mental and substance abuse the leading cause of years lived with disability in a review of global data

Answer 1

Whiteford et al., 2010

Question 2

Action of Gi/o

Answer 2

Inhibit adenyl cyclase (inhibits CAMP) and inhibit VSCCs and activate VSPCs

Question 3

Downstream effects of barr2 recruitment

Answer 3

on SRC and AKT

Question 4

Inhibition of Barr2 results in left shift of morphine dose response curve

Answer 4

Yang et al., 2011

Question 5

Studies have shown that Barr2 knockout attenuates tolerance to morphine and improves its analgesic effects

Answer 5

Yang et al., 2011

Question 6

How do opioids increase DA release

Answer 6

Hyperpolarise inhibitory GABA neuron – disinhibited DAergic neuron

Question 7

Since opioid system is involved in reward, dysregulation may cause…

Answer 7

abberant behaviours such as binge eating and gambling

Question 8

MOP antagonist reduces hedonic response to certain sweetened food and decreases calorific intake - opioid antagonists in binge eating disorderr?

Answer 8

Ziauddeen et al., 2014

Question 9

Also evidence for MOP antag in gambling and drug addictions

Answer 9

Rosenberg et al., 2013, Giuliano et al., 2013

Question 10

Abolishing MOPs prevents the analgesic and conditioned place preference response in mice - reduced reward??

Answer 10

Matthes et al., 1996

Question 11

absence of Barr2 reduces morphine tolerance

Answer 11

Bohn et al., 1999

Question 12

How might Barr2 cause tolerance

Answer 12

Endocytosis

Question 13

Prolonged morphine administration causes constitutively active MOP activity

Answer 13

Wang et al., 2004

Question 14

Increased constituvive activity causes enhanced naloxone induced aversion

Answer 14

Shoblock and Maidment 2006

Question 15

The basal analgesic displayed by Baar2-lacking mice is mediated by constitutive MOP activity - how do we know and who said this?

Answer 15

Lam et al., 2011

Effects are blocked by inverse agonist naloxone but not neutral antagonist

Question 16

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

Answer 16

Lam et al., 2011

Question 17

Barr2 knockouts show decreased side effects including constipation, locomotion, respiratory depression

Answer 17

Urs et al., 2011, Raehal et al., 2005

Question 18

Morphine induced MOP activaton produces locomotion which is attenuated in Barr2 but not Barr1 knockouts

Answer 18

Urs et al., 2011

Question 19

TH-/- mice lack morphine indued locomotion. This is restored by ldopa injection

Answer 19

Hnasko et al., 2005

Question 20

TH-/- mice exhibit mrphine induced conditioned place preference

Answer 20

Hnasko et al., 2005

Question 21

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

Answer 21

Urs et al., 2011

Question 22

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

Answer 22

Urs et al., 2011