Yin-and-yang bifurcation of opioidergic circuits for descending analgesia at the midbrain of the mouse

Abstract

In the descending analgesia pathway, opioids are known to disinhibit the projections from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM), leading to suppression of pain signals at the spinal cord level. The locus coeruleus (LC) has been proposed to engage in the descending pathway through noradrenergic inputs to the spinal cord. Nevertheless, how the LC is integrated in the descending analgesia circuit has remained unknown. Here, we show that the opioidergic analgesia pathway is bifurcated in structure and function at the PAG. A knockout as well as a PAG-specific knockdown of phospholipase C β4 (PLCβ4), a signaling molecule for G protein-coupled receptors, enhanced swim stress-induced and morphine-induced analgesia in mice. Immunostaining after simultaneous retrograde labeling from the RVM and the LC revealed two mutually exclusive neuronal populations at the PAG, each projecting either to the LC or the RVM, with PLCβ4 expression only in the PAG-LC projecting cells that provide a direct synaptic input to LC-spinal cord (SC) projection neurons. The PAG-LC projection neurons in wild-type mice turned quiescent in response to opiates, but remained active in the PLCβ4 mutant, suggesting a possibility that an increased adrenergic function induced by the persistent PAG-LC activity underlies the enhanced opioid analgesia in the mutant. Indeed, the enhanced analgesia in the mutant was reversed by blocking α2-noradrenergic receptors. These findings indicate that opioids suppress descending analgesia through the PAG-LC pathway, while enhancing it through the PAG-RVM pathway, i.e., two distinct pathways with opposing effects on opioid analgesia. These results point to a therapeutic target in pain control.

Lateral hypothalamic fast-spiking parvalbumin neurons modulate nociception through connections in the periaqueductal gray area

“…3d; n = 5 LH PV :ChR2→vlPAG mice, n = 8 LH PV :tdTomato→vlPAG mice; one-way ANOVA Bonferroni multiple comparisons test, ***p = 0.0007) suggesting that LH PV neurons regulate nociceptive processing through connections in the vlPAG. Since neuronal circuits in the PAG are crucial for opioid-induced analgesia 20,21,26,27 , we sought to examine whether the LH PV →vlPAG pathway engages opioidergic mechanisms to promote antinociception. To test this, LH PV :ChR2→vlPAG mice were injected subcutaneously (s.c.) with the μ-opioid receptor antagonist naltrexone (10 mg/kg, s.c.) 30 min prior to photostimulation during the hot plate test.…”

“…We then combined optogenetics and electrophysiology to demonstrate that LH PV neurons are synaptically connected to cells within the vlPAG and that activation of this LH PV →vlPAG pathway also modulates nociceptive responses to both thermal and chemical visceral noxious stimuli. Finally, since the PAG is an important site for opioid-mediated analgesia 20,21,26,27 , we investigated whether modulation of nociception by the LH PV →vlPAG pathway involved opioidergic mechanisms.…”

Cellular Circuits in the Brain and Their Modulation in Acute and Chronic Pain

“…Multiple interactions between the LC-noradrenaline system and drugs affecting pain and analgesia, such as opioids and gabapentinoids, have been described at multiple avenues, including the PAG and the RVM (36). An elegant study recently uncovered that PAG neurons projecting to the LC are distinct from PAG neurons projecting to the RVM in the classical descending inhibitory pathway (152). Interestingly, while the PAG-LC pathway is modulated by opioids to suppress descending inhibition, the PAG-RVM pathway is activated by opioids to potentiate descending inhibition of spinal nociception (152).…”

Involvement of the Ventrolateral Periaqueductal Gray Matter-Central Medial Thalamic Nucleus-Basolateral Amygdala Pathway in Neuropathic Pain Regulation of Rats

“…Previous studies showed that vlPAG was involved in descending inhibitory or facilitatory pain modulatory pathways (Drake et al, 2016 ; Kim et al, 2018 ; Huang et al, 2019 ). Moreover, it has been proposed that an ascending pain pathway involving the vlPAG might exist (Krout and Loewy, 2000 ).…”