Background & Aims

Individuals with histories of traumatic brain injury (TBI) commonly experience headaches, prolonged recovery after injuries and chronic pain. Recent laboratory and clinical data suggest dysregulated central pain-modulating circuits could be involved. We hypothesized that increased nociceptive sensitization in laboratory animals with TBI after subsequent environmental stress or minor soft tissue injury is driven by descending mu-opioid receptor-positive (OPRM+) nociception-facilitating neurons, ON-cells, in the rostral ventromedial medulla (RVM).

Methods

These studies employed a recently developed mouse closed-head model of TBI, well-established models of bright light stress (BLS)-induced headache and incisional pain. Nociceptive sensitization was quantified using mechanical nociceptive thresholds in the periorbital area after BLS, or in the hindpaw after incision in respective cohorts of mice. To examine latent sensitization, naloxone, an opioid receptor antagonist, was administered after the nociceptive thresholds returned to baseline following TBI. In separate experimental cohorts, OPRM+ neurons in RVM (e.g., ON-cells) were lesioned with dermorphin conjugated saporin (Derm-sap), and the animals’ mechanical nociceptive thresholds following BLS and incisional injury were assessed.

Results

In mice with TBI, we observed hindpaw and periorbital allodynia lasting 10-14 days. After hindpaw incision, sensitivity in control mice returned to baseline after 7 days, while mice with prior TBI displayed prolonged allodynia lasting up to 38 days. Similarly, a 15-min BLS exposure elicited periorbital allodynia in mice with prior TBI whilst having no effect on the periorbital sensitivity in control animals without TBI. Furthermore, blockade of central but not peripheral OPRMs led to mechanical sensitization in both hindpaws in mice with prior TBI. Control mice and those with incision-alone did not display hindpaw allodynia after OPRM blockade. Lastly, lesioning of OPRM+ neurons in RVM by Derm-sap, cells associated with nociceptive facilitation, attenuated the development of persistent sensitization after hindpaw incision or BLS exposure in mice with prior TBI.

Conclusions

Collectively, these findings imply that TBI leads to dysfunctional descending pain modulation. The “recovery” of the mechanical nociceptive threshold after TBI is not a simple return to a pre-injury state but rather a progression to a state of latent sensitization of nociception-facilitating neurons in the RVM. Underlying sensitization can be unmasked in animals with TBI by stressors (e.g., surgical incision, bright light) and by opioid receptor antagonism. Finally, lesioning these RVM nociception-facilitating neurons attenuated the development of latent sensitization after TBI. These observations suggest that TBI produces complex dysfunction in central pain modulation, and identifying ways to suppress endogenous pain-facilitating mechanisms may help those with pain after TBI.

References

•Chen Q, Bharadwaj V, Irvine KA, Clark JD. Mechanisms and treatments of chronic pain after traumatic brain injury. Neurochem Int. 2023 Oct 19:105630. doi: 10.1016/j.neuint.2023.105630. Epub ahead of print. PMID: 37865340.
•Chen Q, Sahbaie P, Irvine KA, Clark JD. Mild Traumatic Brain Injury-Induced Augmented Postsurgical Pain Is Driven by Central Serotonergic Pain-Facilitatory Signaling. Anesth Analg. 2023 Apr 21. doi: 10.1213/ANE.0000000000006505. Epub ahead of print. PMID: 37083595.
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•Irvine KA, Sahbaie P, Liang DY, Clark JD. Traumatic Brain Injury Disrupts Pain Signaling in the Brainstem and Spinal Cord. J Neurotrauma. 2018 Jul 1;35(13):1495-1509. doi: 10.1089/neu.2017.5411. Epub 2018 Apr 30. PMID: 29373948.
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•Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care. 2014 Jun;8(2):143-51. doi: 10.1097/SPC.0000000000000055. PMID: 24752199

Presenting Author

QiLiang Chen

Poster Authors

QiLiang Chen

MD, PhD

Stanford Unviersity

Lead Author

E-mail

Topics

  • Mechanisms: Biological-Systems (Physiology/Anatomy)