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Venetia Zachariou on Rewiring Pain: GPCRs, Plasticity and New Therapeutic Frontiers

SCIENTIFIC ABSTRACT

Pain is protective until it is not. When an injury or inflammation persists, the brain adapts, and what began as a warning signal becomes a self sustaining state of sensory hypersensitivity, poor sleep, anxiety, and depression. Venetia Zachariou studies the intracellular mechanisms that hold this state in place, from G protein signaling to histone deacetylation and transcriptional change, across specific brain regions, circuits, and cell types.

A central thread of her work is opioid pharmacology. Opioids remain among the most effective analgesics available, and Venetia Zachariou argues they will always have a place in medicine. The task is to understand what distinguishes the signaling behind analgesia from the signaling behind reward, physical dependence, and addiction, and to use that difference to design safer drugs and entirely new targets.

For Venetia Zachariou, the conviction to stay in science was shaped by a single moment: seeing a published paper report the opposite phenotype to the spinophilin data she had spent years building, and learning at a Gordon conference that both results could be true. Listeners will come away with a clearer view of how chronic pain is maintained and why the most useful answers may lie downstream of the receptor.

ABOUT Dr. Zachariou

Venetia Zachariou is the Edward Avedisian Professor and Chair of the Department of Pharmacology, Physiology & Biophysics at the Boston University Chobanian & Avedisian School of Medicine. She earned her PhD in Pharmacology at the Medical College of Georgia, trained as a postdoctoral fellow with Marina Picciotto at Yale, and spent more than a decade in the Department of Neuroscience at the Icahn School of Medicine at Mount Sinai before moving to Boston in 2023.

Her laboratory combines systems pharmacology, biochemistry, molecular biology, and genetic approaches to identify the processes that maintain chronic pain and to discover new targets for neuropathic and other long lasting pain conditions. A central aim is to define the cellular mechanisms behind opioid physical dependence and analgesic tolerance, and to translate them into interventions that make opioid analgesics safer.

Venetia Zachariou codirects an NIH training program in Biomolecular Pharmacology, is a fellow of ASPET and the American College of Neuropsychopharmacology, and serves on the editorial boards of Biological Psychiatry, Science Signaling, British Journal of Pharmacology, and Molecular Pharmacology.

SCIENTIFIC THEMES OF THE CONVERSATION

• Signaling adaptations that sustain chronic pain

• Separating opioid analgesia from reward, dependence, and addiction

• Looking downstream of the receptor: G proteins, HDACs, and transcription

• The limits of every technique, from knockout mice to cryo EM structures

• Unexpected data, competing results, and the collaborations they create

• Building interdisciplinary lab cultures where trainees thrive

KEY INSIGHTS FROM THE CONVERSATION

Chronic Pain Is Not Prolonged Acute Pain

Acute pain tells the body where an injury is. Once pain persists for months or years, the whole brain adapts, bringing sensory deficits, sleep disruption, anxiety, and depression with it. Venetia Zachariou's goal is not simply to suppress pain signs but to break the cycle that maintains them.

The Answer May Lie Downstream of the Receptor

Even when an animal receives a mu opioid agonist, the lab links its findings to downstream signaling rather than to the receptor itself. Long term drug exposure engages many neurotransmitter systems, so the intracellular adaptations tell a more complete story than any single receptor.

Opioids Will Always Be Medicine

Venetia Zachariou is clear that opioids are not inherently bad; their analgesic power is unmatched. The work is to identify what is unique about analgesic signaling compared with reward and dependence, and collaborations with medicinal chemists on peripherally restricted compounds point one way forward.

Antidepressants Hold a Clue About Speed

Antidepressants relieve chronic pain, partly through effects once dismissed as off target, but they take a long time to work. Understanding the intracellular and transcriptional changes they trigger could lead to drugs that produce the same benefit faster.

An Opposite Result Became a Lifelong Collaboration

After three to four years working on spinophilin and opioid responses in animals that were hard to breed, Venetia Zachariou saw a Science paper on adrenergic receptors describing the opposite role. She brought her figures to Lee Limbird at a Gordon conference, learned that both findings made sense, and went on to exchange plasmids and ideas with first author Qin Wang, who became one of her closest friends and collaborators.

Sometimes Pharmacology Is About Timing

As a graduate student, she spent months unable to make the kappa opioid antagonist norBNI work, delaying her defense. A passing comment over breakfast donuts in the lab next door, to give it two hours ahead of time, solved the problem, and years later that knowledge saved her months of troubleshooting in Eric Nestler's lab.

Every Technique Has a Limitation

On the day of her defense, her advisor's only parting advice was that every technique has a limitation. Knockouts, viral targeting, and cryo EM structures each move the field forward, but none gives all the answers, which is why interdisciplinary collaboration matters so much.

EPISODE TIMELINE

Timestamps were generated using AI for readability.

• 00:00 Introduction

• 01:12 Venetia Zachariou's lab: G proteins, epigenetics, and making opioids safer

• 07:44 A telegraph, a compass, and the move from Athens to Augusta

• 17:36 Academia, industry, and the end of the one way trip

• 22:10 Building an interdisciplinary lab and the GPCR that signals differently in analgesia and reward

• 26:36 Every technique has a limitation: tools, imaging, and analgesics that stay out of the brain

• 31:44 The paper that reported the opposite phenotype

• 34:46 The kappa antagonist that only worked two hours early

• 37:07 Pandemic collaborations and an antidepressant acting through opioid receptors

• 39:37 Advice for young scientists, lab culture, and growing Boston's GPCR community

SELECTED QUOTES

"Opioids have extreme pain alleviating properties, and they're not always bad. They will always be used in medicine. What we have to do is, from the policy to the molecular biology level, make them safer."

Venetia Zachariou

"My advisor came and told me: remember, every technique has a limitation. I was like, really? That's all that you have to tell me? And I know that he was so right."

Venetia Zachariou

"I learned to trust my findings, but I also found that communication is very important."

Venetia Zachariou

"Treat this as an adventure, as a journey. Don't treat it as a job."

Venetia Zachariou