Roles of prefrontal cortex and paraventricular thalamus in affective and mechanical components of visceral nociception.
Visceral pain represents a major clinical challenge in the management of many gastrointestinal disorders, eg, pancreatitis. However, cerebral neurobiological mechanisms underlying visceral nociception are poorly understood. As a representative model of visceral nociception, we applied cerulein hyperstimulation in C57BL6 mice to induce acute pancreatitis and performed a behavioral test battery and c-Fos staining of brains. We observed a specific pain phenotype and a significant increase in c-Fos immunoreactivity in the paraventricular nucleus of the thalamus (PVT), the periaqueductal gray, and the medial prefrontal cortex (mPFC). Using neuronal tracing, we observed projections of the PVT to cortical layers of the mPFC with contacts to inhibitory GABAergic neurons. These inhibitory neurons showed more activation after cerulein treatment suggesting thalamocortical "feedforward inhibition" in visceral nociception. The activity of neurons in pancreatitis-related pain centers was pharmacogenetically modulated by designer receptors exclusively activated by designer drugs, selectively and cell type specifically expressed in target neurons using adeno-associated virus-mediated gene transfer. Pharmacogenetic inhibition of PVT but not periaqueductal gray neurons attenuated visceral pain and induced an activation of the descending inhibitory pain pathway. Activation of glutamatergic principle neurons in the mPFC, but not inhibitory neurons, also reversed visceral nociception. These data reveal novel insights into central pain processing that underlies visceral nociception and may trigger the development of novel, potent centrally acting analgesic drugs.
Department of Internal Medicine 2, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Angela
A
Jurik
Eva
E
Auffenberg
Sabine
S
Klein
Jan M
JM
Deussing
Roland M
RM
Schmid
Carsten T
CT
Wotjak
Christoph K
CK
Thoeringer
D000339:Affect; D000818:Animals; D001522:Behavior, Animal; D002108:Ceruletide / Q000633:toxicity; D000229:Dependovirus; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020644:Midline Thalamic Nuclei / Q000378:metabolism*; D009434:Neural Pathways / Q000378:metabolism; D056325:Neuronal Tract-Tracers; D009474:Neurons / Q000378:metabolism*; D059225:Nociception / Q000502:physiology*; D010195:Pancreatitis / Q000139:chemically induced; D010487:Periaqueductal Gray / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D059265:Visceral Pain / Q000378:metabolism* / Q000523:psychology
D056325:Neuronal Tract-Tracers; D016760:Proto-Oncogene Proteins c-fos; D002108:Ceruletide