Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain
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Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain. / Hansen, Rikke R; Vacca, Valentina; Pitcher, Thomas; Clark, Anna K; Malcangio, Marzia.
In: Pain, Vol. 157, No. 3, 03.2016, p. 666-76.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain
AU - Hansen, Rikke R
AU - Vacca, Valentina
AU - Pitcher, Thomas
AU - Clark, Anna K
AU - Malcangio, Marzia
PY - 2016/3
Y1 - 2016/3
N2 - 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.
AB - 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.
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1097/j.pain.0000000000000416
DO - 10.1097/j.pain.0000000000000416
M3 - Journal article
C2 - 26574822
VL - 157
SP - 666
EP - 676
JO - Pain
JF - Pain
SN - 0304-3959
IS - 3
ER -
ID: 169754757