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.

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Passive leg movement ( PLM )‐induced hyperemia is used to assess the function of the vascular endothelium. This study sought to determine the impact of movement speed and range of motion ( ROM ) on the hyperemic response to PLM and determine if the currently recommended protocol of moving the leg through a 90° ROM at 180°/sec provides a peak hyperemic response to PLM . 11 healthy adults underwent multiple bouts of PLM , in which either movement speed (60–240°/sec) or ROM (30–120° knee flexion) were varied. Femoral artery blood flow (Doppler Ultrasound) and mean arterial pressure ( MAP ; photoplethysmography) were measured throughout. Movement speed generally exhibited positive linear relationships with the hyperemic response to PLM , eliciting ~15–20% increase in hyperemia and conductance for each 30°/sec increase in speed ( P < 0.05). However, increasing the movement speed above 180°/sec was physically difficult and seemingly impractical to implement. ROM exhibited curvilinear relationships ( P <0.05) with hyperemia and conductance, which peaked at 90°, such that a 30° increase or decrease in ROM from 90° resulted in a 10–40% attenuation ( P < 0.05) in the hyperemic response. Alterations in the balance of antegrade and retrograde flow appear to play a role in this attenuation. Movement speed and ROM have a profound impact on PLM ‐induced hyperemia. When using PLM to assess vascular endothelial function, it is recommended to perform the test at the traditional 180°/sec with 90° ROM , which offers a near peak hyperemic response, while maintaining test feasibility.

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