D2 Receptors in the Periaqueductal Gray/Dorsal Raphe Modulate Peripheral Inflammatory Hyperalgesia via the Rostral Ventral Medulla. (21st May 2021)

• Record Type: Journal Article
• Authors: Ferrari, Luiz F.; Pei, JunZhu; Zickella, Michael; Rey, Charles; Zickella, Jacqueline; Ramirez, Anna; Taylor, Norman E.
• Is Part Of: Neuroscience. Volume 463(2021)
• Page Start: 159
• Page End: 173
• Publication Date: 2021-05-21
• Subjects: BNST bed nucleus of the stria terminalis -- CARR carrageenan -- DA dopaminergic -- DREADD direct designer receptor exclusively activated by designer drugs -- NAc nucleus accumbens -- PAG periaqueductal gray -- RVM rostral ventral medulla -- VTA ventral tegmental area; dopamine -- pain -- descending inhibition -- hyperalgesia -- PAG -- RVM; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2021.03.035
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: D-amphetamine produces analgesia by activating dopaminergic neurons in the PAG. Direct activation of D2 dopaminergic receptors in the PAG induces analgesia. PAG D2 dopaminergic neurons-triggered analgesia is mediated through the RVM. GABAergic modulation at the RVM is involved in PAG D2-dependent analgesia. Abstract: Dopamine neurons in the periaqueductal gray (PAG)/dorsal raphe are key modulators of antinociception with known supraspinal targets. However, no study has directly tested whether these neurons contribute to descending pain inhibition. We hypothesized that PAG dopamine neurons contribute to the analgesic effect of D-amphetamine via a mechanism that involves descending modulation via the rostral ventral medulla (RVM). Male C57BL/6 mice showed increased c-FOS expression in PAG dopamine neurons and a significant increase in paw withdrawal latency to thermal stimulation after receiving a systemic injection of D-amphetamine. Targeted microinfusion of D-amphetamine, L-DOPA, or the selective D2 agonist quinpirole into the PAG produced analgesia, while a D1 agonist, chloro APB, had no effect. In addition, inhibition of D2 receptors in the PAG by eticlopride prevented the systemic D-amphetamine analgesic effect. D-amphetamine and PAG D2 receptor-mediated analgesia were inhibited by intra-RVM injection of lidocaine or the GABAA receptor agonist muscimol, indicating a PAG-RVM signaling pathway in this model of analgesia. Finally, both systemic D-amphetamine and local PAG microinjection of quinpirole, inhibited inflammatory hyperalgesia induced by carrageenan. This hyperalgesia was transiently restored by intra-PAG injection of eticlopride, as well as RVM microinjection of muscimol. We conclude that D-amphetamine analgesia is partially mediated by descending inhibition and that D2 receptors in the PAG are responsible for this effect via modulating neurons that project to the RVM. These results further our understanding of the antinociceptive effects of dopamine and elucidate a mechanism by which clinically available dopamine modulators produce analgesia.