Prolonged activation in these receptors are thought to decrease dopamine in the striatum, leading to dysphoria. Also, I have yet to find any link between μ-opioid/k-opioid antagonism and its therapeutic effects on ADHD from the studies I've read so far. So for now, I believe that the therapeutic effects are coming from atomoxetine’s NET inhibition(which raises DA in PFC), NMDA antagonism & downstream GABAA upregulation.
From Wikipedia
4-Hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors. It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.
While we observed no activation of the μ-receptor(data not shown). The partial κ-opioid agonism of 4-hydroxyatomoxetine may have a clinical correlate upon long-term exposure of atomoxetine in the treatment of ADHD. It is known that prolonged activation of κ-opioid receptors due to chronic administration of a κ-opioid agonist results in the development of physical dependence and withdrawal symptoms upon cessation. Also, κ-opioid agonists are known to cause CNS-related adverse events, most notably dysphoria.
NMDA antagonism
Atomoxetine is classified as a non-competitive NMDA receptor antagonist. NMDA antagonism is inhibitory in nature thereby'turning off' various neurotransmitters in the brain. Thus, it acts as an anxiolytic and probably is how it’s treating the racing thoughts in ADHD and anxiety disorder by quietening the mind.
Pseudo-anticholinergic
This is the dry mouth and constipation that resembles traditional anticholinergics. But there are no studies indicating that pseudo-anticholinergics can lead to dementia. This is a result of NET inhibition which reduces parasympathetic cholinergic tones. Fortunately, these side effects are supposed to lessen over time for most people. More info available on Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Application:https://goo.gl/Eq8MrU
Summaryofthetext-book
Stimulation of noradrenergic receptors in the sympathetic nervous system may also cause a net reduction of parasympathetic cholinergic tone, since these systems often have reciprocal roles in peripheral organs and tissues. Thus increased norepinephrine activity at alpha 1 receptors may produce symptoms reminiscent of"anticholinergic" side effects. This is not due to direct blockade of muscarinic cholinergic receptors but to indirect reduction of net parasympathetic tone due to increaesd sympathetic tone. Thus, a"pseudo-anticholinergic" syndrome of dry mouth, constipation, and urinary retention may be caused by high degress of NET inhibition, even though SNRIs have no direct actions on muscarini cholinergic receptors. Usually, however, the indirect reduction of cholinergic tone yields milder symptoms than does direct blockade of muscarinic cholinergic receptors.
Thus, virtually all side effects of the selective NET inhibition can be understood as undesirable actions of norepinephrine in undesirable pathways at undesirable receptor sub-types. Just as for the SSRIs, this occurs because it is not possible for a systemically administered drug to act only at the desirable receptors in the desirable places; it must act everywhere it is distrubuted, which means all over the brain and all over the body. Fortunately, side effects from NET inhibition are more of a nuisance than a danger and they generally attenuate over time, although they can cause an important subset of patients to discontinue treatment.
Both groups of rats were given Strattera for 21 days. In the early treatment group, they analysed the rats brain brain immediately. And in the late treatment group, after the 21 days, they were left alone for 3 weeks before being analysed. It was found that there were more profound gene expression changes in the late treatment group. And further 3 months later when they analysed the rats brain again, some of the gene expression returned to normal while others amplified and stayed permanent. Source: http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/24348020
Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat: A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder: https://www.nature.com/articles/1395936.pdf
μ-opioid antagonism/k-opioid partial agonism
NMDA antagonism
Pseudo-anticholinergic