237) Periaqueductal Gray Dopaminergic Neurons Modulate Peripheral Inflammatory Hyperalgesia

Abstract

Neural dopamine (DA) modulators such as ᴅ-amphetamine and methylphenidate provide a promising new approach to treating pain. Though the mechanism by which they produce analgesia is poorly understood, these psychostimulants are antinociceptive and counteract the opioid-induced side effects of respiratory depression and sedation. Despite their potential, DA-modulating drugs have never been adopted clinically for pain relief, possibly due to a lack of understanding their mechanism of action. Considering previous evidence of a role of DA neurons from the periaqueductal gray (PAG) in pain modulation, we hypothesized that PAG DA neurons are antinociceptive and contribute significantly to the analgesic effect of ᴅ-amphetamine via descending spinal cord inhibition at the rostral ventral medulla (RVM). Male C57BL/6 mice that had received carrageenan in the hind paw were treated intraperitoneally with ᴅ-amphetamine, and its analgesic effect was compared with the analgesia produced by morphine. Separate groups of mice were stereotaxically prepared with infusion cannula targeted to either the PAG or RVM. We observed that the inhibition of thermal hyperalgesia in the mouse model of carrageenan-induced inflammatory pain by systemic ᴅ-amphetamine (6mg/kg) was similar to that produced by morphine (3mg/kg), and that ᴅ-amphetamine increased cFOS expression in PAG DA neurons. Targeted microinfusion of ᴅ-amphetamine, L-DOPA, or a selective D2 receptor agonist, but not a D1 agonist, into the PAG also attenuated thermal hyperalgesia, suggesting a role for D2 receptors in PAG-mediated analgesia. Finally, systemic ᴅ-amphetamine-mediated analgesia was prevented when neural transmission through the RVM was inhibited by local pretreatment with the GABAA receptor agonist muscimol. These findings indicate a modulatory role of D2 receptors and descending inhibition through GABAergic receptors at the RVM in ᴅ-amphetamine-mediated analgesia. Importantly, they indicate that the use of stimulants could enhance pain control, potentially as an alternative to opioids, avoiding the deleterious side-effects responsible for the current opioid crisis.