The Role of Glutamatergic and Dopaminergic Neurons in the Periaqueductal Gray/Dorsal Raphe: Separating Analgesia and Anxiety

Abstract

The periaqueductal gray (PAG) is a significant modulator of both analgesic and fear behaviors in both humans and rodents, but the underlying circuitry responsible for these two phenotypes is incompletely understood. Importantly, it is not known if there is a way to produce analgesia without anxiety by targeting the PAG, as modulation of glutamate or GABA neurons in this area initiates both antinociceptive and anxiogenic behavior. While dopamine (DA) neurons in the ventrolateral PAG (vlPAG)/dorsal raphe display a supraspinal antinociceptive effect, their influence on anxiety and fear are unknown. Using DAT-cre and Vglut2-cre male mice, we introduced designer receptors exclusively activated by designer drugs (DREADD) to DA and glutamate neurons within the vlPAG using viral-mediated delivery and found that levels of analgesia were significant and quantitatively similar when DA and glutamate neurons were selectively stimulated. Activation of glutamatergic neurons, however, reliably produced higher indices of anxiety, with increased freezing time and more time spent in the safety of a dark enclosure. In contrast, animals in which PAG/dorsal raphe DA neurons were stimulated failed to show fear behaviors. DA-mediated antinociception was inhibitable by haloperidol and was sufficient to prevent persistent inflammatory pain induced by carrageenan. In summary, only activation of DA neurons in the PAG/dorsal raphe produced profound analgesia without signs of anxiety, indicating that PAG/dorsal raphe DA neurons are an important target involved in analgesia that may lead to new treatments for pain.

Activation of ventrolateral orbital cortex improves mouse neuropathic pain–induced anxiodepression

“…The PAG is thought to be a fundamental region that was involved in defensive and antinociceptive behaviors. The vlPAG, a subdivision of the PAG, has been shown to participate in not only analgesia and defensive behavior in response to threat, but also stress-induced anxiodepressive-like behaviors (64,65). The frontal cortex, including the VLO, has been shown to preferentially target ventral PAG, particularly the vlPAG (35,66), which is further confirmed by the retrograde and anterograde virus tracking in the present study.…”

A Midbrain Circuit that Mediates Headache Aversiveness in Rats

“…In addition, TH(+) neurons can co-release glutamate, which has been demonstrated in the PAG projection to the bed nucleus of the stria terminalis (Li et al, 2016a). Activation of PAG dopamine neurons have overall demonstrated antinociceptive effects (Li et al, 2016a; Taylor et al, 2019), but we cannot rule out the possibility that a small subset projecting to the VTA might participate in a pronociceptive, projection-specific effect.…”

“…The PAG also contains dopamine neurons that play a role in pain and reward behaviors (Li et al, 2016a; Taylor et al, 2019). Omelchenko and Sesack (2010) found that only 3% of PAG axons in the VTA contain dopamine (Omelchenko and Sesack, 2010).…”

dmPFC-vlPAG projection neurons contribute to pain threshold maintenance and antianxiety behaviors

“…The vlPAG is a significant modulator of both analgesic and fear behaviors in humans and rodents. Previous studies have showed that specific activation of VGLUT2containing neurons in the vlPAG produced obvious analgesia and freezing behavior (28,41). Tovote et al reported that this freezing behavior was produced by activation or disinhibition of vlPAG excitatory outputs to pre-motor targets in the magnocellular nucleus (Mc) of the medulla (28).…”