Morphine treatment accelerates sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer.
Metastatic bone cancer causes severe pain that is primarily treated with opioids. A model of bone cancer pain in which the progression of cancer pain and bone destruction is tightly controlled was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced, rather than diminished, spontaneous, and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or tumor burden in vivo but accelerated sarcoma-induced bone destruction and doubled the incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity and upregulated IL-1 beta within the femurs of sarcoma-treated mice suggesting enhancement of sarcoma-induced osteolysis. These results indicate that sustained morphine increases pain, osteolysis, bone loss, and spontaneous fracture, as well as markers of neuronal damage in DRG cells and expression of pro-inflammatory cytokines. Morphine treatment may result in "add-on" mechanisms of pain beyond those engaged by sarcoma alone. While it is not known whether the present findings in this model of osteolytic sarcoma will generalize to other cancers or opioids, the data suggest a need for increased understanding of neurobiological consequences of prolonged opioid exposure which may allow improvements in the use of opiates in the effective management of cancer pain.
King
Tamara
T
Department of Pharmacology, College of Medicine, University of Arizona HSC, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA.
Vardanyan
Anna
A
Majuta
Lisa
L
Melemedjian
Ohannes
O
Nagle
Ray
R
Cress
Anne E
AE
Vanderah
Todd W
TW
Lai
Josephine
J
Porreca
Frank
F
D000701:Analgesics, Opioid / Q000009:adverse effects / Q000627:therapeutic use; D000818:Animals; D018771:Arthralgia / Q000139:chemically induced* / Q000473:pathology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005598:Fractures, Spontaneous / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009020:Morphine / Q000009:adverse effects* / Q000627:therapeutic use; D010014:Osteolysis / Q000139:chemically induced* / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology
D000701:Analgesics, Opioid; D009020:Morphine
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