Substance P and NK-1 receptors have been implicated in peripheral mechanisms of inflammatory pain, central sensitization and inhibition, opioid analgesia, and affective-motivational aspects of pain. The investigative methods thus far were mostly limited to the nociceptive sub-systems level (molecular, physiological, innate behavioral response measures). Less studied is the net effect of all the contributions of NK-1 receptors at the level where integration into a pain experience takes place. This study used a thermal operant escape test to compare cortically mediated (learned) nociceptive escape responses of wild-type and NK-1R knockout balb/c mice of both sexes. Experiment 1 investigated the stimulus intensity response relationship covering a range from nociceptive cold (2 and 8 deg C) to neutral (36 deg C) and finally to nociceptive hot (44 and 46 deg C) temperatures: NK-1 receptor deficient mice of both sexes were less sensitive to nociceptive cold than their wild-type counterparts. No statistically significant group difference was found in the hot nociceptive range. Experiment 2 assessed the analgesic effect of systemic morphine in the presence or absence of NK-1 receptors: morphine 1mg/kg, injected subcutaneously, produced a statistically significant analgesic affect only in wild-type mice at 44 deg C (female group: p<0.001; male group: p=0.0019). No statistically significant analgesic effect was seen in any of the NK-1 receptor-deficient groups. The analgesic effect of morphine, calculated as % Maximum Possible Effect (%MPE) was smaller in NK-1 receptor-deficient animals (male and female groups combined) compared to their wild-type counterparts (p=0.033). Higher morphine doses produced effects that were not nociceptive-specific: at 2mg/kg the activity of the animals in the operant test was also affected at the non-nociceptive temperature of 36 deg C.