Benzos vs Opioids and analgesia

[WSH]

http://www.psychiatrictimes.com/addiction/benzodiazepines-and-chronic-pain

Further, the findings certainly fit with our knowledge that benzodiazepines can interfere with the analgesic effects of opioids and can cause hyperalgesia.

Benzodiazepine mediated antagonism of opioid analgesia

Activation of supraspinal gamma-aminobutyric acid-A (GABAA) receptors is known to result in antagonism of opioid analgesia

Since benzos and opioids are both "downers", shouldn't Benzos actually increase the analgesic effects of opioids in the layman terms of "the combo of two downers knocking you out even more, therefore even less perception of pain".

But I know that that's a very primitive logic and that the opioid and GABA systems are complexly interacting (both in the brain and also in the dorsal horn [an important pain center, maybe even the most important one]).

Does anybody have an explanation of this "paradoxical" effect of benzos reducing opioid analgesia and even inducing hyperalgesia (i.e. increasing pain)?

 

[Kdem]

The former is somewhat credible in the sense that benzodiazepine tolerance/dependece could decrease the effectiveness of an opiate, possibly depending on the benzodiazepine.

The second one isn't worth much IMO. The evidence isn't great, but flumazenil can be a mild agonist at the 'benzodiazepine receptor'. Weak source, the best I can do in a minute or so: 'Flumazenil is a weak partial agonist in some animal models of activity' https://www.drugs.com/pro/flumazenil-injection.html

Anecdotal evidence is weak and mixed, but possibly flumazenil might work in cases of benzodiazepines withdrawal 'addiction' by displacing the original benzodiazepine and acting as a weak agonist. I've read a report describing mild anxiolytic effects.

 

[Cotcha Yankinov]

Mu agonists work not just at the level of direct action at the spinal cord but also in areas like the periaqueductal gray - MORs are expressed pre-synaptically on GABAergic releasing terminals where they act to decrease GABA release via effects on potassium and calcium channels, this seems to be responsible for a lot of the analgesia

There is some component of post-synaptic MOR activation to analgesia but I think its thought that most of it is due to inhibition of GABA release, oddly enough

 

[WSH]

Mu agonists work not just at the level of direct action at the spinal cord but also in areas like the periaqueductal gray - MORs are expressed pre-synaptically on GABAergic releasing terminals where they act to decrease GABA release via effects on potassium and calcium channels, this seems to be responsible for a lot of the analgesia

There is some component of post-synaptic MOR activation to analgesia but I think its thought that most of it is due to inhibition of GABA release, oddly enough

Oh, so by decreasing GABA release, the activity of the periaqueductal gray is increased and that then again decreases the activity of e.g. the dorsal horn, causing that pain does not enter the cortex (via the thalamus).

 

[Cotcha Yankinov]

Indeed, I'm fuzzy on the ultimate circuit level of action but I'm assuming that either the periaqueductal gray sends efferents down directly or communicates with other areas that send inhibitory efferents down that synapse onto dorsal horn

I'm under the impression that SNRIs MAO for relieving neuropathic pain was due to boosting inhibitory efferents as well

 

[Kdem]

Cotcha,

It's not my thread, but what does MOR stand for ?

 

[Cotcha Yankinov]

Hey there, MOR is Mu-opioid receptor, the main opioid receptors responsible for opioid euphoria and analgesia

 

[Kdem]

Thanks.

I guess that´s one example of how screwed I am. Put it simply, clonazepam blocks signals to the thalamus. http://jn.physiology.org/content/71/6/2576 is one example and relatively simple.

(´causing that pain does not enter the cortex (via the thalamus).´)

It can be a very effective painkiller ... in practical terms, opiate tolerance can go through the roof.