A clinical area pooling painful situations in which tolerance and hyperalgesia are associated (Mercadante and Portenoy, 2001) is emerging in cancer pain therapy. In this area Bruera (1995) defined the clinical issues of two opposite painful situations: nociceptive pain (opioid responsive) and neuropathic pain (opioids poorly responsive). Only in the last years, experimental in vivo models, have been applied to study the molecular mechanisms of cancer pain.
Schwei et al. (1999), implanted osteolytic sarcoma cells into the marrow space of mouse femur.
After twenty-two days the palpation on the cancerous femur produced typical pain behaviours (movement evoked and hyperalgesia), before any significant bone destruction is evident, related to early central sensitization (Luger et al. 2001).
Luger et al. (2002), on the same model, tested the efficacy of morphine on pain and hyperalgesia. The dosages of morphine to control bone cancer pain were ten fold superior to those requested to control the same pain intensity in the inflammatory model. Thus suggests a foundamental difference in the mechanisms of these two kinds of pain.
Based on the expression of functional opioid receptors by the tumor cells (Zagon et al., 1987; Maneckjee et al., 1990) we hypothesised that the tumor cells, binding opioids, may cause a peculiar kind of opioid tolerance (Arcuri, 1998).
Recently we have been demonstrate:
1)The selective morphine uptake by tumours growing in nude mice (Arcuri et al., 2002).
2)The generation of NO by tumor cells in response to morphine binding to I opioid receptors (Fimiani et al., 1999).
Because of the NO role in the mechanisms of tolerance and hyperalgesia (Kolesnikov et al., 1993) it is conceivable that the NO levels released in the tumor microenvironment are a key factor determining the declining (tolerance) or paradoxical (hyperalgesia) opioid responsiveness during the development of cancer pain.
Recent and yet unpublished results seem to confirm this hypothesis.