Opioidergic and GABAergic mechanisms in the rostral ventromedial medulla modulate the nociceptive response of vocalization in guinea pigs

Abstract

Vocalization generated by the application of a noxious stimulus is an integrative response related to the affective-motivational component of pain. The rostral ventromedial medulla (RVM) plays an important role in descending pain modulation, and opiates play a major role in modulation of the antinociception mediated by the RVM. Further, it has been suggested that morphine mediates antinociception indirectly, by inhibition of tonically active GABAergic neurons. The current study evaluated the effects of the opioids and GABA agonists and antagonists in the RVM on an affective-motivational pain model. Additionally, we investigated the opioidergic–GABAergic interaction in the RVM in the vocalization response to noxious stimulation. Microinjection of either morphine (4.4 nmol/0.2 μl) or bicuculline (0.4 nmol/0.2 μl) into the RVM decreased the vocalization index, whereas application of the GABA A receptor agonist, muscimol (0.5 nmol/0.2 μl) increased the vocalization index during noxious stimulation. Furthermore, prior microinjection of either the opioid antagonist naloxone (2.7 nmol/0.2 μl) or muscimol (0.25 nmol/0.2 μl) into the RVM blocked the reduction in vocalization index induced by morphine. These observations suggest an antinociceptive and pro-nociceptive role of the opioidergic and GABAergic neurotransmitters in the RVM, respectively. Our data show that opioids have an antinociceptive effect in the RVM, while GABAergic neurotransmission is related to the facilitation of nociceptive responses. Additionally, our results indicate that the antinociceptive effect of the opioids in the RVM could be mediated by a disinhibition of tonically active GABAergic interneurons in the downstream projection neurons of the descending pain control system; indicating an interaction between the opioidergic and GABAergic pathways of pain modulation.