Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain

Hong Zhang, Dominique M. Lund, Haley A. Ciccone, William D. Staatz, Mohab M. Ibrahim, Tally M. Largent-Milnes, Herbert H. Seltzman, Igor Spigelman, Todd W Vanderah

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain. Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients' quality of life. By contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP. Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP. Our studies using a syngeneic murine model of CIBP show that both acute and sustained administration of a peripherally restricted CB1R agonist, 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI), significantly alleviated spontaneous pain behaviors in the animals. This analgesic effect by PrNMI can be reversed by a systemic administration but not spinal injection of SR141716, a selective CB1R antagonist. In addition, the cancer-induced bone loss in the animals was not exacerbated by a repeated administration of PrNMI. Furthermore, catalepsy and hypothermia, the common side effects induced by cannabinoids, were measured at the supratherapeutic doses of PrNMI tested. PrNMI induced mild sedation, yet no anxiety or a decrease in limb movements was detected. Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects. Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP.

Original languageEnglish (US)
Pages (from-to)1814-1823
Number of pages10
JournalPain
Volume159
Issue number9
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

Fingerprint

Cannabinoid Receptor Agonists
Bone Neoplasms
Cannabinoid Receptor CB1
Analgesics
Pain
rimonabant
Bone and Bones
Breast Neoplasms
Catalepsy
Spinal Injections
Animal Behavior
Cannabinoids
Hypothermia
Chronic Pain
Opioid Analgesics
Extremities
Anxiety
Quality of Life

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Zhang, H., Lund, D. M., Ciccone, H. A., Staatz, W. D., Ibrahim, M. M., Largent-Milnes, T. M., ... Vanderah, T. W. (2018). Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Pain, 159(9), 1814-1823. https://doi.org/10.1097/j.pain.0000000000001278

Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. / Zhang, Hong; Lund, Dominique M.; Ciccone, Haley A.; Staatz, William D.; Ibrahim, Mohab M.; Largent-Milnes, Tally M.; Seltzman, Herbert H.; Spigelman, Igor; Vanderah, Todd W.

In: Pain, Vol. 159, No. 9, 01.09.2018, p. 1814-1823.

Research output: Contribution to journalArticle

Zhang, H, Lund, DM, Ciccone, HA, Staatz, WD, Ibrahim, MM, Largent-Milnes, TM, Seltzman, HH, Spigelman, I & Vanderah, TW 2018, 'Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain', Pain, vol. 159, no. 9, pp. 1814-1823. https://doi.org/10.1097/j.pain.0000000000001278
Zhang H, Lund DM, Ciccone HA, Staatz WD, Ibrahim MM, Largent-Milnes TM et al. Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Pain. 2018 Sep 1;159(9):1814-1823. https://doi.org/10.1097/j.pain.0000000000001278
Zhang, Hong ; Lund, Dominique M. ; Ciccone, Haley A. ; Staatz, William D. ; Ibrahim, Mohab M. ; Largent-Milnes, Tally M. ; Seltzman, Herbert H. ; Spigelman, Igor ; Vanderah, Todd W. / Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. In: Pain. 2018 ; Vol. 159, No. 9. pp. 1814-1823.
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