Roles of α₁- and α₂-adrenoceptors in the nucleus raphe magnus in opioid analgesia and opioid abstinence-induced hyperalgesia

Noradrenaline and α-adrenoceptors have been implicated in the modulation of pain in various behavioral conditions. Noradrenergic neurons and synaptic inputs are present in neuronal circuits critical for pain modulation, but their actions on neurons in those circuits and consequently the mechanisms underlying noradrenergic modulation of pain remain unclear. In this study, both recordings in vitro and behavioral analyses in vivo were used to examine cellular and behavioral actions mediated by α₁- and α₂-adrenoceptors on neurons in the nucleus raphe magnus. We found that α₁- and α₂-receptors were colocalized in the majority of a class of neurons (primary cells) that inhibit spinal pain transmission and are excited during opioid analgesia. Activation of the α₁-receptor depolarized whereas α ₂-receptor activation hyperpolarized these neurons through a decrease and an increase, respectively, in potassium conductance. Blockade of the excitatory α₁-receptor or activation of the inhibitory α₂-receptor significantly attenuated the analgesia induced by local opioid application, suggesting that α₁-receptor-mediated synaptic inputs in these primary cells contribute to their excitation during opioid analgesia. In the other cell class (secondary cells) that is thought to facilitate spinal nociception and is inhibited by analgesic opioids, only α₁-receptors were present. Blocking the α ₁-receptor in these cells significantly reduced the hyperalgesia (increased pain) induced by opioid abstinence. Thus, state-dependent activation of α₁-mediated synaptic inputs onto functionally distinct populations of medullary pain-modulating neurons contributes to opioid-induced analgesia and opioid withdrawal-induced hyperalgesia.