title: Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain.
abstract: Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient pain relief and often lead to significant adverse effects. In models of cancer-induced bone pain, pathological sprouting of sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in the dorsal horn of the spinal cord. We observed that calcitonin gene-related peptide (CGRP)-fiber sprouting in the bone was associated with an increase in CGRP content in sensory neuron cell bodies in the dorsal root ganglia (DRG) and increased basal and activity-evoked release of CGRP from their central terminals in the dorsal horn. Intrathecal administration of a peptide antagonist (α-CGRP8-37) attenuated referred allodynia in the hind paw ipsilateral to bone cancer. CGRP receptor components (CLR and RAMP1) were up-regulated in dorsal horn neurons and expressed by reactive astrocytes. In primary cultures of astrocytes, CGRP incubation led to a concentration-dependent increase of forskolin-induced cAMP production, which was attenuated by pretreatment with CGRP8-37. Furthermore, CGRP induced ATP release in astrocytes, which was inhibited by CGRP8-37. We suggest that the peripheral increase in CGRP content observed in cancer-induced bone pain is mirrored by a central increase in the extracellular levels of CGRP. This increase in CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling but also act on astrocytic CGRP receptors and lead to release of ATP.
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom CNR, National Research Council, Cell Biology and Neurobiology Institute, Rome, Italy IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Rikke R
authors.initials: RR
authors.lastname: Hansen
authors.forename: Valentina
authors.initials: V
authors.lastname: Vacca
authors.forename: Thomas
authors.initials: T
authors.lastname: Pitcher
authors.forename: Anna K
authors.initials: AK
authors.lastname: Clark
authors.forename: Marzia
authors.initials: M
authors.lastname: Malcangio
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D015740:Calcitonin Gene-Related Peptide / Q000502:physiology*; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009924:Organ Culture Techniques; D010146:Pain / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology
chemical_list: D015740:Calcitonin Gene-Related Peptide