Development of a macaque model of central post–stroke pain and challenges to understand the mechanisms

Abstract

Central post–stroke pain (CPSP) is a central neuropathic pain characterized by pain and sensory abnormalities due to central nervous system lesion following a cerebro vascular accident. Developing therapeutic interventions for CPSP is difficult because its pathophysiology is unclear. In recent years, rodent models of CPSP have been developed to address this problem. In these models, a lesion of the thalamus including the ventral posterolateral nucleus (VPL) was made by inducing a focal stroke. Using these models, cellular and molecular mechanisms that underlie pathogenesis of CPSP have been discovered. Moreover, some drugs have been suggested to ameliorate the symptoms of the rodent CPSP models. In addition to the rodent models, a primate model of CPSP might also contribute to overcoming CPSP because it is more com-patible with humans in regard to the structures and functions of brain regions which is suggested to be involved in pain in humans. Aside from humans, the macaque monkeys are the most widespread primate genus, ranging from Japan to North Africa. Since the macaque monkeys are the animal species closest to humans among those which can be used for invasive experiments, they are widely used to understand the mechanisms of the human brain. Therefore, we developed a nonhuman primate model of CPSP using macaque monkeys. Because there were individual differences among macaque monkeys, the location of the VPL in each monkey was determined by magnetic resonance imaging (MRI) and extracellular recording of neuronal activity during tactile stimulation. Thereafter, a hemorrhagic lesion was induced by injecting collagenase type IV. Histological analysis using Nissl staining revealed that most of the lesion was localized within the VPL. Several weeks after the injection, the macaques displayed behavioral changes that were interpreted as reflecting the development of both mechanical allodynia and thermal hyperalgesia. functional magnetic resonance imaging is performed to detect brain activity changes underlying CPSP using the established macaque model. The combination of the homology of pain–related cortical areas between macaques and humans with relative-ly large macaque brain enables acquisition of imaging data on par with those examined in clinical research. Therefore, the brain imaging studies using the macaque monkey provide an advantage for the translation of the findings to human patients. We believe that animal models of CPSP will contribute not only to full understanding of pathophysiology but also to the development of therapeutic interventions for it.