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<p>The nocebo effect, opposite of the better-known placebo effect, in which anticipation of harm worsens pain and other symptoms, is increasingly thought to be responsible for poor clinical outcomes. In humans, nocebo hyperalgesia (i.e., increased pain sensitivity) is blocked by proglumide, a cholecystokinin (CCK) receptor antagonist. Yet, the neural circuitry underlying nocebo hyperalgesia remains unidentified, largely due to a lack of appropriate animal models. Here, we developed distinct&#xa0;mouse models of CCK-dependent nocebo hyperalgesia in which the expectation of pain was elicited by contextual or social cues. We find that these nocebo paradigms share a neural circuit involving CCK release from neurons projecting from the anterior cingulate cortex to the lateral periaqueductal gray. This pathway could represent a promising target for therapeutic interventions in pain-related disorders.</p>

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Cholecystokinin input from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Sandra J. Poulson,
  • Aleksandrina Skvortsova,
  • Fatama Tuz Zahra,
  • Damien C. Boorman,
  • Seyed Asaad Karimi,
  • Lisiê V. Paz,
  • Wanning Cui,
  • Antonietta Mandatori,
  • Jacob Burek,
  • Zahra Siddiqi,
  • Maryam I. Fazili,
  • Shivani R. Gami,
  • Oakley B. Morgan,
  • Mélanie Di Maria,
  • Anton Dinh,
  • Lianfang Liang,
  • Robert Contofalsky,
  • Jeffrey S. Mogil,
  • Loren J. Martin

摘要

The nocebo effect, opposite of the better-known placebo effect, in which anticipation of harm worsens pain and other symptoms, is increasingly thought to be responsible for poor clinical outcomes. In humans, nocebo hyperalgesia (i.e., increased pain sensitivity) is blocked by proglumide, a cholecystokinin (CCK) receptor antagonist. Yet, the neural circuitry underlying nocebo hyperalgesia remains unidentified, largely due to a lack of appropriate animal models. Here, we developed distinct mouse models of CCK-dependent nocebo hyperalgesia in which the expectation of pain was elicited by contextual or social cues. We find that these nocebo paradigms share a neural circuit involving CCK release from neurons projecting from the anterior cingulate cortex to the lateral periaqueductal gray. This pathway could represent a promising target for therapeutic interventions in pain-related disorders.