Evidence of a role for descending serotonergic facilitation in a rat model of cancer-induced bone pain

Descending modulation of spinal processing plays an important role in chronic pain states. Monoamine pathways comprise a major component of descending controls from the brainstem to the spinal cord. Recent emphasis has been on facilitatory actions mediated by the 5-HT3 receptor. We investigated the effects of spinally administered ondansetron, a selective 5-HT3 receptor antagonist, on electrical- and natural-evoked dorsal horn (DH) neuronal responses in a rat model of cancer-induced bone pain (CIBP). Injection of MRMT-1 cells into the tibiae of Sprague–Dawley rats was used to model CIBP, whilst sham-operated rats were injected with the cell medium alone. Behavioural testing at regular intervals monitored the development of mechanical allodynia, cold allodynia, and ambulatory-evoked pain. In vivo electrophysiology experiments were carried out 15–17 days after surgery, when there were significant behavioural and neuronal alterations in the cancer animals. Spinally administered ondansetron (10, 50, and 100 μg) had no effect on electrical-evoked neuronal responses, but significantly reduced mechanical- and thermal-evoked responses in both the groups of animals. Furthermore, the effects of ondansetron were significantly greater in cancer animals compared to shams. These results therefore suggest a role for descending serotonergic facilitation in CIBP.This work was supported by The Wellcome Trust and Pfizer Ph.D. studentship.Peer reviewe

Efficacy of chronic morphine in a rat model of cancer-induced bone pain: Behavior and in dorsal horn pathophysiology

Morphine is one of the main analgesics in cancer-induced bone pain (CIBP). To investigate the efficacy of morphine in CIBP and alteration in dorsal horn pathophysiology, systemic morphine was administered (3 mg/kg) bi-daily between days 11 and 15 after MRMT-1 carcinoma cell injections (compared with a single injection (3 mg/kg) of morphine on day 15, and acute spinal morphine (0.1, 1, 10 μg/50 μL). The chronic systemic morphine schedule significantly attenuated pain behavior (von Frey 15 g; P < .01) to a greater extent than acute systemic morphine (von Frey 15 g; P < .05). In vivo electrophysiology (day 15 chronic systemic morphine) showed an attenuation of hyperexcitable wide dynamic range (WDR) neurons, but the abnormal raised WDR to nociceptive specific neuronal ratio remained. Acute spinal morphine attenuated electrical and natural WDR neuronal response in shams at a lower dose (1 μg) compared with cancer (10 μg). Chronic morphine is more effective at attenuating pain-related behaviors than single doses, although the dorsal horn retains a pathophysiologic characterization.Peer reviewe

The prognostic role of circulating tumor cells in heavily pretreated individuals with a low life expectancy

ABSTRACT  Aims: Studies of circulating tumor cells (CTCs) have generally recruited individuals with newly diagnosed metastatic cancer, with recent data also indicating their prognostic value in the adjuvant setting. Their role in dying patients has not been established. Experimental: CTCs were measured in 43 individuals with metastatic breast cancer estimated to have less than 6 months to live who had exhausted standard therapeutic options. Results: Those with a CTC count of ≤100 had a median of 182 days to live, compared with those with a CTC count of &gt;100 who had a median of 17 days until death (p = 0.009, log rank, HR: 3.1, 95% CI: 1.4–7.3). Conclusion: A CTC count of &gt;100 is associated with imminent death. Provided external validity is demonstrated, such information would be useful for patients and their families who often request specific prognostic clarity and could improve the quality of end-of-life care. </jats:p