23 The enzyme monoamine PD0332991 cost oxidase (MAO)-B exists on the outer mitochondrial membrane, occurring predominantly in astrocytes.24 When astrocytes become activated (as customarily defined by their greatly enhanced glial fibrillary acidic protein (GFAP) binding) they express high levels of MAO-B,25 thereby providing an indirect target for PET imaging. L-deprenyl
(selegeline) is a selective irreversible MAO-B inhibitor that has been carbon-11-labeled, Inhibitors,research,lifescience,medical allowing for PET imaging of astrocyte activity.26 A deuterium substitution on the L-deprenyl molecule causes a significant reduction in the rate of trapping, thereby further enhancing the tracer’s sensitivity to subtle changes in MAO-B concentration.27 Thus far, studies using this deuterium-substituted deprenyl (DED) tracer have been performed to assess MAO-B function and astrocytosis in epilepsy,28 amyotrophic lateral sclerosis,29 Creutzfeldt–Jakob disease,30 and Alzheimer’s disease.31 No study to date has utilized MAO-B expression to image spinal cord Inhibitors,research,lifescience,medical or brain astrocyte involvement in human pain. Microglia are the resident macrophages of the brain and spinal cord and thus act as the first and main form of active immune Inhibitors,research,lifescience,medical defense in the central nervous system. Microglia rapidly activate in response to a variety
of pathological conditions, including nerve damage and persistent pain.20 Microglial activation is characterized Inhibitors,research,lifescience,medical by cellular responses including specific morphological changes, proliferation, increased or de novo expression of cell surface markers or receptors, and migration to the site of injury.32 Activated microglia express translocator protein
(TSPO), which has been observed in animal models of neuropathic pain both in the dorsal horns of the spinal cord,33 the spine,34 and in cortex.35 In human studies, increased TSPO expression has been reported in the thalamus after peripheral nerve injuries36 and in widespread cortical regions after traumatic brain Inhibitors,research,lifescience,medical injury.37 PRB28, a second-generation, high-affinity TSPO radioligand suitable for imaging of microglial activation in neuroinflammation,38 is currently being explored for pain imaging. MAO-B expression occurs primarily in astrocytes, while TSPO expression occurs only in activated microglia and to a lesser degree in active astrocytes. Compared with the microglial response to nerve injury, astrocyte proliferation begins relatively late and progresses slowly but is sustained for more than 5 months, a time-frame paralleling the development of chronic pain.39 Unlike microglia, astrocytes form networks with themselves and are closely associated with neurons and blood vessels, a close contact that makes it possible for astrocytes to regulate the external chemical environment of neurons during synaptic transmission. Moreover, there is recent evidence that spinal astrocytes but not microglia contribute to the pathogenesis of painful neuropathy.