The existence of a wide variety of neuropeptides within the spinal cord dorsal horn raises the question of their possible roles in sensory processing. The present series of behavioral experiments examined the effects of intrathecal (IT) administration of two such neuropeptides, thyrotropin-releasing hormone (THR) and vasopressin (VAS), on pain sensitivity and antinociception. TRH exerted no marked effect on basal pain sensitivity over the dose range examined (0.25 ng–2.5 μg). However, a U-shaped dose-response effect on morphine antinociception (3 μg, IT) was observed, wherein potent attenuation, moderate attenuation, or enhancement of morphine-induced anticiception was observed following the various doses tested. In contrast, VAS produced non-opiate antiniception at the highest doses tested (25 ng and 250 ng) and none of the VAS doses (0.25ng–250 ng) appeared to interact with IT morphine (3 μg) antinociception. Lastly, IT TRH was not observed to interact with IT VAS antinociception. These data provide evidence that these neuropeptides exert strikingly different effects on pain sensitivity and opiate antinociception, and provide initial evidence that TRH may be included in the growing list of neuropeptides that can act endogenous opiate antagonists within the central nervous system.