Brain Glutamate, Dopamine, anxiety and pain

pattismith

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"Activation of glutamatergic neurons, however, reliably produced higher indices of anxiety, with increased freezing time and more time spent in the safety of a dark enclosure.

In contrast, animals in which PAG/dorsal raphe DA neurons were stimulated failed to show fear behaviors.

DA-mediated antinociception was inhibitable by haloperidol and was sufficient to prevent persistent inflammatory pain induced by carrageenan.

In summary, only activation of DA neurons in the PAG/dorsal raphe produced profound analgesia without signs of anxiety, indicating that PAG/dorsal raphe DA neurons are an important target involved in analgesia that may lead to new treatments for pain."

The Role of Glutamatergic and Dopaminergic Neurons in the Periaqueductal Gray/Dorsal Raphe:

Separating Analgesia and Anxiety


Norman E. Taylor,
1 JunZhu Pei,2 Jie Zhang,1 Ksenia Y. Vlasov,2 Trevor Davis,3 Emma Taylor,4 Feng-Ju Weng,2 Christa J. Van Dort,5 Ken Solt,5 and Emery N. Brown5,6



Abstract

The periaqueductal gray (PAG) is a significant modulator of both analgesic and fear behaviors in both humans and rodents, but the underlying circuitry responsible for these two phenotypes is incompletely understood.

Importantly, it is not known if there is a way to produce analgesia without anxiety by targeting the PAG, as modulation of glutamate or GABA neurons in this area initiates both antinociceptive and anxiogenic behavior.

While dopamine (DA) neurons in the ventrolateral PAG (vlPAG)/dorsal raphe display a supraspinal antinociceptive effect, their influence on anxiety and fear are unknown.

Using DAT-cre and Vglut2-cre male mice, we introduced designer receptors exclusively activated by designer drugs (DREADD) to DA and glutamate neurons within the vlPAG using viral-mediated delivery and found that levels of analgesia were significant and quantitatively similar when DA and glutamate neurons were selectively stimulated.

Activation of glutamatergic neurons, however, reliably produced higher indices of anxiety, with increased freezing time and more time spent in the safety of a dark enclosure.

In contrast, animals in which PAG/dorsal raphe DA neurons were stimulated failed to show fear behaviors.

DA-mediated antinociception was inhibitable by haloperidol and was sufficient to prevent persistent inflammatory pain induced by carrageenan.

In summary, only activation of DA neurons in the PAG/dorsal raphe produced profound analgesia without signs of anxiety, indicating that PAG/dorsal raphe DA neurons are an important target involved in analgesia that may lead to new treatments for pain.
 

pattismith

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Interesting to note the link between mu opioid receptors (blocked by Naltrexone) and Dopamine receptors.

We found that µ-opioid receptor-induced antinociception (DAMGO, 0.3 μg) from PAG was blocked by the coadministration of either D1-like or D2-like dopaminergic antagonists (SCH23390, 2, 4, and 6 μg or raclopride, 2 and 4 μg, respectively) both in the tail-flick and in the mechanical paw-withdrawal test.

A selective D2-like receptor agonist (piribedil, 6 and 12 μg into the PAG) induced antinociception in the mechanical paw-withdrawal test, but not in the tail-flick test.

This effect was blocked by the coadministration of its selective antagonist (raclopride 4 μg), as well as by either a GABAA agonist (muscimol, 0.1 μg) or an opioid receptor antagonist (naloxone, 0.5 μg).

A selective D1-like receptor agonist (SKF38393, 1, 5, and 10 μg into the PAG) induced a poor and transient antinociceptive effect, but when combined with piribedil, a potentiated antinociceptive effect emerged.

None of these treatments affected locomotion in the open-field test.

These findings suggest that µ-opioid antinociception from the PAG depends on dopamine acting on both D1-like and D2-like receptors.

Selective activation of PAG D2-like receptors induces antinociception mediated by supraspinal mechanisms dependent on inhibition of GABAA and activation of opioid neurotransmission.

Dopaminergic mechanisms in periaqueductal gray-mediated antinocic...: Ingenta Connect
these articles explain why dopaminergic drugs are analgesic and naltrexone is hyperalgesic for me;

Interestingling, I can revert the hyperalgesic/headache effect I get from LDN by taking methylphenidate (dopaminergic)....