Figure 2.

Summary diagram illustrating a significant supraspinal contribution to secondary, but not primary, thermal hyperalgesia after peripheral inflammation. Peripheral injury results in activation and sensitization of peripheral nociceptors and subsequent enhanced excitability of dorsal horn nociceptive neurons (central sensitization) that contributes to primary hyperalgesia (at site of injury) and secondary hyperalgesia (adjacent/distant from site of injury). Additionally, it is proposed that stimulation of nociceptors activates a spinobulbospinal loop, engaging a centrifugal descending nociceptive facilitatory influence from the RVM. Facilitatory influences are activated by NMDA receptors and NO^⋅, and neurotensin (NT) receptors in the RVM and descend to multiple spinal segments to contribute significantly to secondary hyperalgesia. In contrast, primary hyperalgesia does not involve descending facilitatory influences from supraspinal sites and is likely the direct result of peripheral nociceptor sensitization and neuroplasticity intrinsic to the spinal cord. For clarity, the afferent input to the spinal dorsal horn from the site of injury is illustrated as not entering the spinal cord (which it certainly does).