Ca you explain Tramadol's MOA?

[dangit]

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In First Aid (p. 430), it says tramadol inhibits serotonin and NE re-uptake, but in general, opioids inhibit the release of neurotransmitter.

If I understand this correctly, in order to inhibit neurotransmission, wouldn't you want to prevent neurotransmitters from being in the extracellular area (ie synaptic cleft)? So, by decreasing the presence of neurotransmitter, you prevent neurotransmissions and thus pain sensation.

But why is it that for tramadol, it inhibits neurotransmitter reuptake, which essentially keeps neurotransmitters around. Wouldn't that keep NT around and thus promote neurotransmission?

Can someone please explain?

Thank you!

 

[Slade]

I had to look this us. According to Wiki, tramadol has a multitude of mechanisms (opioid receptor agonist along with serotonin releasing agent and NE reuptake inhibitor, and at least 5 other MOAs). Although no one is quite sure how the drug works, it is thought that tramadol's primary metabolite is a potent opioid receptor agonist (among other mechs) and that it is this mechanism that provides the pain relief.
Otherwise you are right in that inhibiting the reuptake of NE would lead to increased neurotransmission.

I think in this situation, it is a case of what mechanism dominates over the others.

Hope that helps!

 

[bbydoc]

But why is it that for tramadol, it inhibits neurotransmitter reuptake, which essentially keeps neurotransmitters around. Wouldn't that keep NT around and thus promote neurotransmission?

Can someone please explain?

Thank you!

Rand and Dale says this:
Tramadol, a metabolite of the antidepressant trazodone (Ch. 39), is widely used as an analgesic for postoperative pain. It is a weak agonist at μ-opioid receptors, and also a weak inhibitor of noradrenaline reuptake.

later on it also mentions that exact mechanism of analgesia is not understood.

read also somewhere that general opioid antagonists like naloxone do not inhibit tramadol fully, so its mechanism should be different from general opioids.

 

[bluesTank]

When thinking about pharmacology in general, it is important to remember that cells all have different receptors.

I'm not sure of an exact answer to your question, but while it is true that mu receptors hyperpolarize neurons, they may not be present on the cells in which 5HT and NE act upon.

 

[2Bee]

In addition to central opiate receptor agonist activity, tramadol exerts norepinephrine and serotonin reuptake inhibition in the CNS, which inhibits pain transmission in the spinal cord. The monoaminergic reuptake blockade, similar to MAOIs, is an important contribution to the analgesic and adverse event profile of tramadol. The inhibitory reuptake effects of tramadol on norepinephrine and serotonin are 100—1000 times less than those of imipramine.

 

[Zoom-Zoom]

So you might vaguely recall from neuro that in addition to the ascending pain afferents there are also descending pathways from the brainstem that inhibit pain reception in the spinal cord. It's like pain negative feedback.

The two main descending pathways are from the Locus Coeruleus (sp?) and the Periaqueductal Grey/Raphe nucleus.

The LC is the main source of NE in the central nervous system. So it's descending fibers are noradrenergic and somehow inhibit firing down in the spine.

The PAG activates the Raphe nucleus which is a major source of 5HT in the CNS. These fibers also descend down on interneurons in the spine.

With neuro meds and especially opiates, MOA's are super vague because we really don't know what we're doing..we just know the meds work. But it can be assumed that tramadol might ramp up the above two pathways in addition to it's opiate effects. Hope that helps.