Mu-opioid receptor-positive neurons in rostral ventromedial medulla drive pain sensitization after traumatic brain injury in both male and female mice

Persistent headache and pain hypersensitivity are common after mild traumatic brain injury (mTBI). However, the central mechanisms that support posttraumatic pain sensitization are not fully understood. The rostral ventromedial medulla (RVM), a key output node of the endogenous pain modulation system, contains mu-opioid receptor-positive (Oprm+) pain-facilitating neurons that are important in chronic pain.

Here, we investigated whether these neurons are essential for post-mTBI pain behaviors, vulnerability to persistent headache and postsurgical pain, and latent sensitization in mice. Male and female mice received dermorphin-saporin to lesion RVM Oprm+ neurons or blank-saporin as controls, then underwent mTBI or sham-TBI treatment. Periorbital and hindpaw mechanical sensitivity were measured.

After recovery, vulnerability to persistent periorbital and hindpaw allodynia was assessed using bright-light stress (BLS) and hindpaw incision, respectively. Latent sensitization was assessed by administering naloxone 100 days post-mTBI. mTBI caused acute periorbital and hindpaw allodynia, unaffected by RVM Oprm+ neuron lesioning. However, lesioning of RVM Oprm+ neurons prevented reinstatement of periorbital and hindpaw allodynia after BLS, incision or naloxone, with effects conserved across sexes.

RVM Oprm+ neurons support persistent post-mTBI pain sensitization. Their dysregulation after mTBI may increase an individual’s vulnerability to headache, persistent postsurgical pain, and latent pain sensitization. QiLiang Chen, MD, PhD was supported in part by Career Development Award IK2BX006567 and David Clark, MD, PhD was supported in part by I02BX007171 from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service.

Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, 300 Pasteur Drive, Room H3580 MC 5640, Stanford, CA, 94305, USA QiLiang Chen, Peyman Sahbaie, Karen-Amanda Irvine & J. David Clark Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave (E4-220), Palo Alto, CA, 94304, USA The authors declare no competing interests. All experiments were performed in accordance with the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Palo Alto VA Institutional Animal Care and Use Committee.

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