Dopaminergic mechanisms in periaqueductal gray-mediated antinociception

Abstract

As important as perceiving pain is the ability to modulate this perception in some contextual salient situations. The periaqueductal gray (PAG) is perhaps the most important site of endogenous pain modulation; however, little is known about dopaminergic mechanisms underlying PAG-mediated antinociception. In this study, we used a pharmacological approach to evaluate this subject. 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.

The Distinct Functions of Dopaminergic Receptors on Pain Modulation: A Narrative Review

“…Selective activation of D2-like receptors within the PAG significantly reduced allodynia, which was also blocked by GABAA receptor agonist (muscimol), opioid receptor antagonist (naloxone), and D2-like receptor antagonist (raclopride). Although the analgesic effect induced by activating D1-like receptors in the PAG was tiny and transient, it enhanced the antinociceptive effects of D2-like receptors [114]. Notably, treatments with all drugs had no significant influence on the locomotion of rats observed in open-field tests.…”

“…The effect was observed by the behaviors integrated supraspinal response (examined by hot plate test), but not the simple spinal reflex (examined by the tail-immersion test) [111]. Additionally, several studies have found that injection of both D2-like and D1-like receptor antagonists (raclopride and SCH-23390, respectively) into the PAG reduced antino-ciception induced by the activation of μ-opioid receptors [114]. Selective activation of D2-like receptors within the PAG significantly reduced allodynia, which was also blocked by GABAA receptor agonist (muscimol), opioid receptor antagonist (naloxone), and D2-like receptor antagonist (raclopride).…”

Painful stimulation increases spontaneous blink rate in healthy subjects

“…Dopaminergic mimetics showed analgesic effects in tonic pain conditions 52,53 . In addition, the coadministration of either D1-like or D2-like dopaminergic antagonists was able to block µ-opioid receptor-induced antinociception 29 . The hypothesis that SBR modulation due to laser stimuli is due to the activation of antinociceptive mechanisms is also supported by the observation of an inverse correlation between individual SBR changes and subjective pain perception, as assessed by the NRS.…”

“…The selective activation of D2 receptors led to decreased nociception, increasing the pain threshold in a transitory or lasting manner according to the experimental conditions. This effect depends on supraspinal mechanisms involving GABA-A and opioid neurotransmission 29 . Conversely, blocking dopamine receptors within the nucleus accumbens inhibited antinociception 30 .…”

“…A subpopulation of dopaminergic neurons within the ventrolateral periaqueductal grey (PAG), a brain area included in the descending pain modulatory system 20 , projects to brain regions known to be involved in pain modulation [21][22][23][24] . Both D1-like and D2-like dopamine receptors are expressed within the ventrolateral PAG [25][26][27] and have been shown to contribute to antinociception 15,[28][29][30] .…”