GABAAergic inhibition or dopamine denervation of the A11 hypothalamic nucleus induces trigeminal analgesia

Abstract

Descending pain-modulatory systems, either inhibitory or facilitatory, play a critical role in both acute and chronic pain. Compared with serotonin and norepinephrine, little is known about the function of dopamine (DA). We characterized the anatomical organization of descending DA pathways from hypothalamic A11 nuclei to the medullary dorsal horn (MDH) and investigated their role in trigeminal pain. Immunochemistry analysis reveals that A11 is a heterogeneous nucleus that contains at least 3 neuronal phenotypes, DA, GABA, and alpha-calcitonin gene-related peptide (α-CGRP) neurons, exhibiting different distribution patterns, with a large proportion of GABA relative to DA neurons. Using fluorogold, we show that descending pathways from A11 nuclei to MDH originate mainly from DA neurons and are bilateral. Facial nociceptive stimulation elevates Fos immunoreactivity in both ipsilateral and contralateral A11 nuclei. Fos immunoreactivity is not detected in DA or projecting neurons but, interestingly, in GABA neurons. Finally, inactivating A11, using muscimol, or partially lesioning A11 DA neurons, using the neurotoxin 6-hydroxydopamine, inhibits trigeminal pain behavior. These results show that A11 nuclei are involved in pain processing. Interestingly, however, pain seems to activate GABAergic neurons within A11 nuclei, which suggests that pain inhibits rather than activates descending DA controls. We show that such inhibition produces an antinociceptive effect. Pain-induced inhibition of descending DA controls and the resulting reduced DA concentration within the dorsal horn may inhibit the transfer of nociceptive information to higher brain centers through preferential activation of dorsal horn D2-like receptors.

Three Types of A11 Neurons Project to the Rat Spinal Cord

“…These results indicate that A11 dopaminergic neurons are mainly regulated or modulated by a PV-lacking subgroup of GABAergic neurons. In addition, we did not detect any PV-IR cell bodies within the A11 region, in spite of several reports demonstrating that GABAergic neurons are present in this region [8,32,33]. Taken together, these results may indicate that non-PV-IR GABAergic neurons within or outside the A11 region regulate the activity of dopaminergic neurons of the A11 region.…”

“…Our study revealed that coronal sections from the rostral levels of the A11 region contained short PV-IR processes that varied in direction, while the caudal levels of the A11 region contained long PV-IR processes in the perpendicular direction, indicating that processes observed in the rostral aspects of A11 were extending in the rostro-caudal direction and processes observed in the caudal aspects were extending in the ventral-dorsal direction. These results indicate that the A11 region has morphological heterogeneity along the rostral-caudal axis and part of the functional heterogeneity suggested by previous studies [7,8] may attribute to the differential morphological property between the rostral and caudal aspect of the A11 region, such as different origin of inputs or differential connectivity of neurons in each subregion.…”

“…For instance, GABAergic neurons in the rostral to middle aspect of the A11 region are activated when facial nociceptive stimulation is applied [8]. TH neurons of the caudal A11 region are more responsible for dopamine release at the rat spinal cord than those of the rostral A11 region [7].…”

“…For example, Pappas et al demonstrated that neurons in the caudal aspect of the A11 region have more responsibility for dopamine release at the spinal cord than those in the rostral aspect [7]. Abdallah et al demonstrated that neurons in the rostral to middle aspect of the A11 region are more activated than those in the caudal part during migraine [8]. However, it is unknown whether the A11 region has heterogeneity in its morphological organization.…”

Synergistic effect of spexin and progesterone on pain sensitivity attenuation in ovariectomized rats

“…In this area, several enzymatic pathways for production of steroids and neurosteroids exist. These chemicals induce the expression of GABA‐A, NMDA and P2X receptors in spinal cord and play a pivotal role in pain modulation . The wide distribution of neurosteroids in spinal cord dorsal horn also supports this hypothesis .…”