Objective: Chronic pain is associated with increased incidence of hypertension. Sleep deprivation, common in patients with chronic pain, is associated with increased blood pressure and heart rate. This study was designed to determine whether sleep deprivation induces increased cardiovascular responses to pain. In addition; we examined the role of melatonin and endorphins in mediating these responses. Method: The study was conducted in Sprague-Dawely rats divided into a control group (n=8) and Rapid Eye Moment sleep deprived (REMSD) group (n=8). REM sleep deprivation was done for three days using the inverted flowerpot technique. Systolic BP and HR were recorded at baseline as well as 5, 10 and 30 minutes after intra-plantar formalin injection. In addition, serum melatonin and endorphin levels were determined. Results: Under basal conditions, BP and HR and following acute pain (1st phase of formalin injection) were comparable with non-sleep deprived (non-SD) state. In contrast, the REMSD rats showed significantly greater increases in HR and BP during the 2nd phase of formalin pain as compared to non-SD state. These changes were associated with significant reductions in serum melatonin and endorphin levels in REMSD rats. Conclusion: These data indicate that exaggerated blood pressure and HR responsiveness to pain in sleep deprivation could be mediated through reductions in melatonin and endorphin