Biology subjects

Livrizzi, G.

Publications and source records attributed to Livrizzi, G..

3 recordsLinked to original sources

bioRxiv2025

Top-down control of the descending pain modulatory system drives placebo analgesia

In placebo analgesia, prior experience and expectations lead to pain suppression by the administration of an inert substance, but causal evidence for its neural basis is lacking. To identify the underlying neural circuits, we reverse-translated a conditioned placebo protocol from humans to mice. Surprisingly, the placebo effect suppresses both nociception and unconditioned emotional-motivational pain-related behavior. Descending pain modulatory neurons in the periaqueductal gray (PAG) are critical for both morphine and placebo antinociception. The placebo effect depends on input to the PAG from the medial prefrontal and anterior cingulate cortices, but not anterior insular cortex. Conditioning enhances noxious stimulus-evoked endogenous opioid release in the PAG to produce analgesia. Our results suggest that cortical control of the descending pain modulatory system (DPMS) is gated by rapid endogenous opioid signaling in the PAG during placebo trials. This study bridges clinical and preclinical research, establishing a central role for the DPMS in placebo analgesia.

neuroscience↗

bioRxiv2023

Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation

The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, we establish that noradrenergic neurons of the locus coeruleus (LC) are essential for supraspinal opioid antinociception. Unexpectedly, given prior emphasis on descending serotonergic pathways, we find that opioid antinociception is primarily driven by excitatory output from the ventrolateral periaqueductal gray (vlPAG) to the LC. Furthermore, we identify a previously unknown opioid-sensitive inhibitory input from the rostroventromedial medulla (RVM), the suppression of which disinhibits LC neurons to drive spinal noradrenergic antinociception. We also report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings significantly revise current models of the DPMS and establish a novel supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation. TeaserConvergent synaptic activation of noradrenergic neurons in the locus coeruleus drives systemic opioid antinociception.

neuroscience↗

bioRxiv2023

In vivo photopharmacology with light-activated opioid drugs

Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed PhOX and PhNX, photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry during chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action. HighlightsA photoactivatable opioid agonist (PhOX) and antagonist (PhNX) for in vivo photopharmacology. Systemic pro-drug delivery followed by local photoactivation in the brain. In vivo photopharmacology produces behavioral changes within seconds of photostimulation. In vivo photopharmacology enables all-optical pharmacology and physiology.

neuroscience↗