Analgesia targeting IB4-positive neurons in cancer-induced mechanical hypersensitivity

J Pain. 2012 Jun;13(6):524-31. doi: 10.1016/j.jpain.2012.01.006. Epub 2012 Apr 5.


Cancer patients often suffer from pain and most will be prescribed μ-opioids. μ-opioids are not satisfactory in treating cancer pain and are associated with multiple debilitating side effects. Recent studies show that μ and δ opioid receptors are separately expressed on IB4 (-) and IB4 (+) neurons, which control thermal and mechanical pain, respectively. In this study we investigated IB4 (+) and IB4 (-) neurons in mechanical and thermal hypersensitivity in an orthotopic mouse oral cancer model. We used a δ opioid receptor agonist and a P2X(3) antagonist to target IB4 (+) neurons and to demonstrate that this subset plays a key role in cancer-induced mechanical allodynia, but not in thermal hyperalgesia. Moreover, selective removal of IB4 (+) neurons using IB4-saporin impacts cancer-induced mechanical but not thermal hypersensitivity. Our results demonstrate that peripherally administered pharmacological agents targeting IB4 (+) neurons, such as a selective δ-opioid receptor agonist or P2X(3) antagonist, might be useful in treating oral cancer pain.

Perspective: To clarify the mechanisms of oral cancer pain, we examined the differential role of IB4 (+) and IB4 (-) neurons. Characterization of these 2 subsets of putative nociceptors is important for further development of effective clinical cancer pain relief.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Carcinoma, Squamous Cell / complications
  • Cell Line, Tumor
  • Disease Models, Animal
  • Humans
  • Hyperalgesia / etiology
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology*
  • Lectins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mouth Neoplasms / complications
  • Neoplasm Transplantation
  • Neoplasms, Experimental / complications*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / physiopathology
  • Nociception / drug effects*
  • Nociception / physiology
  • Pain / drug therapy
  • Pain / etiology
  • Pain / metabolism
  • Pain / physiopathology
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Receptors, Opioid, mu / metabolism


  • Analgesics
  • Lectins
  • Receptors, Opioid, mu