mitogen
Bluelighter
- Joined
- Nov 8, 2004
- Messages
- 127
This is one of my favourite topics. I thought I'd just start the thread and get people to post references, interesting papers they've found. If I remember to, I'll post up the essay I wrote last year on interactions between cannabinoids/CB signaling and opioids/opioid signaling.
There is all sorts of interesting data, like rats that are given cannabinoid agonists during 'adolescence' (what exactly is rodent adolescence?) are considerably more susceptible to the reinforcing effects of opioids adminstered in adulthood than are controls. CB1 agonists reduce morphine withdrawal syndrome. Co-localisation of CB1 and MOR in interesting places, etc. etc.
The paper I'd like to start with is called "GHB ameliorates naloxone-induced conditioned place aversion and physical aspects of morphine withdrawal in mice."
Psychopharmacology (Berl). 2004 Dec;177(1-2):130-40. Epub 2004 Jun 4.
I'll read it after I have a coffee and post some comments on it. Unfortunately I have to be here until about 7pm. Started a 3 hour culture induction at 3:45pm... Oh well, serves me right for coming in at 11am this morning. *sigh*
they say "Numerous observations suggest that GHB may interfere with the brain systems responsible for the expression of the acute reinforcing properties of drugs of abuse and for the expression of the neuroadaptive changes in the dependence process."
They then go on to say that studies regarding the action of GHB on mesolimbic dopamine transmission are conflicting.
So, the idea of this study is to test the effect of GHB on the motivating aspect of opioid withdrawal, since studies have already shown that GHB can ameliorate the physical symptoms of opioid WD.
Naloxone administration is paired with an environmental stimulus (place,) and in the first experiment the ability of GHB to attenuate naloxone induced conditioned place aversion (CPA) was measured. In the second experiment the effect of GHB on the physical symptoms of morphine withdrawal was evaluated. Mice were morphine dependent in the first experiment as well as the second, if that wasn't clear. I'm not sure if naloxone can induce CPA in non-dependent animals. In fact, I remember reading that administration of naloxone to a non-opioid dependent individual does very little, apart from reducing their pain threshold slightly (IIRC). They do a control using a group of non-morphine dependent mice to test the level of CPA induced by these drugs in the absence of dependence.
This experiment appears to be pretty well controlled IMO (though I'm not a psychopharm guy): "Furthermore, with the aim of verifying how removing morphine would affect the expression of conditioning, one group of dependent mice conditioned with naloxone did not receive morphine on the test day."
For the second experiment they used paw tremor (the mouse shakes its paws with lateral movements), body shakes (the mouse shakes its body), jumping (all feet losing contact with the ground), body care (the mouse licks or scratches its fur or paws and cleans its face with the forepaws), genital grooming (the mouse licks its genitalia), ptosis (closing of the eyelids), piloerection (erection of the hair), and diarrhea (presence of soft stool). The time the mice spent performing these behaviours was measured, as was the mass of each mouse to determine if weight loss had occured.
Anyway enough of methods I just wanted to give people an idea of what the experimenters did if they can't be bothered looking up the actual paper.
Discussion stuff:
GHB is great for both the physical and motivational aspects of morphine withdrawal. "When physical signs of morphine withdrawal are
studied, GHB is also effective in decreasing the intensity of these signs to near control levels." - Wow!
I suppose the problem would be people simply moving to GHB as the drug of choice, or if relapse occurs, taking GHB along with their opioid of choice. I understand that GHB and opioids would be REALLY effective at inhibiting firing of the central pattern generator that drives breathing in the respirtory control centre. Shame, really - it sounds like it could be a good buzz.
GHB counters both expression AND acquisition of CPA in mice. That is blocks acquisition is the part I find interesting.
"Administration of GHB to saline-treated animals does not induce either preference or aversion with our laboratory model of conditioned preference." - interesting... that must be pretty rare for a dependence producing drug to not induce CPP.
However, they then go on to say "There is no agreement regarding the rewarding properties of GHB. In contrast with opioids, a greater number of trials seems to be required before preference can be observed after GHB administration (Martellota et al. 1997; Itzhak and Ali 2002) using higher doses than those in our study. Thus, in some circumstances GHB seems to be able to induce positive reinforcing effects in drug-naïve mice." I don't really get their logic there to be honest... I would certainly be surprised if GHB really did not induce CPP. There should be more literature on this...
hmmm, they say "naloxone, although at doses higher than those used in these experiments, is capable of inducing CPA in the absence of morphine," which contradicts my previou statement.
"Clinical reports are also not indicative of true cross-dependency between GHB and opiates." Well sure, they're different drugs. Depends what they mean by 'true cross-dependency.' Perfect cross-dependency doesn't necessarily even occur between say, methadone and morphine. Morphine induced tolerance doesn't involve downregulation at the receptor level, while other opioids do (etorphine,) for example (can't be bothered finding reference. if you specifically want it and cant find it, ask me).
They propose that GHB's attenuation of physical and motivational aspects of morphine withdrawal a.) involves different structures and different mechanisms, and that b.) the motivational effects could be mediated by DA or GABA or both (duhh).
So that's about it. I think the most interesting point raised is the uncertainty about the reinforcing effects of GHB and its effect of mesolimbic DA transmission - all the conflicting studies and all.
There is all sorts of interesting data, like rats that are given cannabinoid agonists during 'adolescence' (what exactly is rodent adolescence?) are considerably more susceptible to the reinforcing effects of opioids adminstered in adulthood than are controls. CB1 agonists reduce morphine withdrawal syndrome. Co-localisation of CB1 and MOR in interesting places, etc. etc.
The paper I'd like to start with is called "GHB ameliorates naloxone-induced conditioned place aversion and physical aspects of morphine withdrawal in mice."
Psychopharmacology (Berl). 2004 Dec;177(1-2):130-40. Epub 2004 Jun 4.
I'll read it after I have a coffee and post some comments on it. Unfortunately I have to be here until about 7pm. Started a 3 hour culture induction at 3:45pm... Oh well, serves me right for coming in at 11am this morning. *sigh*
they say "Numerous observations suggest that GHB may interfere with the brain systems responsible for the expression of the acute reinforcing properties of drugs of abuse and for the expression of the neuroadaptive changes in the dependence process."
They then go on to say that studies regarding the action of GHB on mesolimbic dopamine transmission are conflicting.
So, the idea of this study is to test the effect of GHB on the motivating aspect of opioid withdrawal, since studies have already shown that GHB can ameliorate the physical symptoms of opioid WD.
Naloxone administration is paired with an environmental stimulus (place,) and in the first experiment the ability of GHB to attenuate naloxone induced conditioned place aversion (CPA) was measured. In the second experiment the effect of GHB on the physical symptoms of morphine withdrawal was evaluated. Mice were morphine dependent in the first experiment as well as the second, if that wasn't clear. I'm not sure if naloxone can induce CPA in non-dependent animals. In fact, I remember reading that administration of naloxone to a non-opioid dependent individual does very little, apart from reducing their pain threshold slightly (IIRC). They do a control using a group of non-morphine dependent mice to test the level of CPA induced by these drugs in the absence of dependence.
This experiment appears to be pretty well controlled IMO (though I'm not a psychopharm guy): "Furthermore, with the aim of verifying how removing morphine would affect the expression of conditioning, one group of dependent mice conditioned with naloxone did not receive morphine on the test day."
For the second experiment they used paw tremor (the mouse shakes its paws with lateral movements), body shakes (the mouse shakes its body), jumping (all feet losing contact with the ground), body care (the mouse licks or scratches its fur or paws and cleans its face with the forepaws), genital grooming (the mouse licks its genitalia), ptosis (closing of the eyelids), piloerection (erection of the hair), and diarrhea (presence of soft stool). The time the mice spent performing these behaviours was measured, as was the mass of each mouse to determine if weight loss had occured.
Anyway enough of methods I just wanted to give people an idea of what the experimenters did if they can't be bothered looking up the actual paper.
Discussion stuff:
GHB is great for both the physical and motivational aspects of morphine withdrawal. "When physical signs of morphine withdrawal are
studied, GHB is also effective in decreasing the intensity of these signs to near control levels." - Wow!
I suppose the problem would be people simply moving to GHB as the drug of choice, or if relapse occurs, taking GHB along with their opioid of choice. I understand that GHB and opioids would be REALLY effective at inhibiting firing of the central pattern generator that drives breathing in the respirtory control centre. Shame, really - it sounds like it could be a good buzz.
GHB counters both expression AND acquisition of CPA in mice. That is blocks acquisition is the part I find interesting.
"Administration of GHB to saline-treated animals does not induce either preference or aversion with our laboratory model of conditioned preference." - interesting... that must be pretty rare for a dependence producing drug to not induce CPP.
However, they then go on to say "There is no agreement regarding the rewarding properties of GHB. In contrast with opioids, a greater number of trials seems to be required before preference can be observed after GHB administration (Martellota et al. 1997; Itzhak and Ali 2002) using higher doses than those in our study. Thus, in some circumstances GHB seems to be able to induce positive reinforcing effects in drug-naïve mice." I don't really get their logic there to be honest... I would certainly be surprised if GHB really did not induce CPP. There should be more literature on this...
hmmm, they say "naloxone, although at doses higher than those used in these experiments, is capable of inducing CPA in the absence of morphine," which contradicts my previou statement.
"Clinical reports are also not indicative of true cross-dependency between GHB and opiates." Well sure, they're different drugs. Depends what they mean by 'true cross-dependency.' Perfect cross-dependency doesn't necessarily even occur between say, methadone and morphine. Morphine induced tolerance doesn't involve downregulation at the receptor level, while other opioids do (etorphine,) for example (can't be bothered finding reference. if you specifically want it and cant find it, ask me).
They propose that GHB's attenuation of physical and motivational aspects of morphine withdrawal a.) involves different structures and different mechanisms, and that b.) the motivational effects could be mediated by DA or GABA or both (duhh).
So that's about it. I think the most interesting point raised is the uncertainty about the reinforcing effects of GHB and its effect of mesolimbic DA transmission - all the conflicting studies and all.
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