Differential brainstem circuits mediating conditioned pain modulation induced analgesia and hyperalgesia: A cross-sectional, ultra-high field functional magnetic resonance imaging study

Whilst preclinical studies have identified multiple brainstem sites that can modulate noxious information, the precise location and function of such sites in humans remains unresolved. One method to explore pain modulatory circuits in humans is through the use of the conditioned pain modulation paradigm. Conditioned pain modulation occurs when the intensity of one noxious stimulus is modulated by the application of a second noxious stimulus. Whilst conditioned pain modulation has been primarily used to explore pain inhibition, it can also evoke pain facilitation. Whether the same circuits are involved in both inhibition and facilitation remains unknown. We used ultra-high field functional magnetic resonance imaging to determine brainstem networks responsible for inhibitory and facilitatory conditioned pain modulation responses in 44 pain-free individuals. In 17 individuals pain decreased (inhibitors), in 11 individuals pain increased (facilitators), and 16 individuals displayed no pain intensity change. Analysis of brainstem signal changes revealed that whilst pain decreases were associated with signal intensity decreases in the subnucleus reticularis dorsalis, A5 cell group and locus coeruleus, pain increases were associated with no A5 signal change, but signal decreases in subnucleus reticularis dorsalis and locus coeruleus. Meanwhile, linear correlation analysis revealed midbrain periaqueductal gray matter signal changes that were negatively correlated and rostral ventromedial medulla signal changes that were positively correlated with pain intensity changes with both hypoalgesia and hyperalgesia. Our results suggest the existence of two brainstem networks whereby some regions respond in an on-off manner whereas others are linearly correlated with changes in pain intensity. PERSPECTIVE: This article presents the brainstem circuitry underpinning pain decreases and increases evoked by conditioned pain modulation paradigm. Since brainstem analgesic circuitry is thought to be dysfunctional in individuals with chronic pain, our data provides a platform for exploring such dysfunction.