Pharmacologic characteristics of a medullary hyperalgesic center

The effects of ethylketazocine, U-50,488, morphine and (-)-nicotine administered both i.p. and into the mid-fourth ventricle of intact rats were investigated using a conventional high intensity tail-flick reflex and one evoked with a lower intensity thermal stimulus. The sensitivity of the low intensity thermally evoked tail avoidance reflex was several times that of a high intensity tail-flick reflex in detecting the analgesic activity of morphine and yielded valid assays and relative potencies between morphine (1), EKC (18.76) and U-50,488 (0.23) when the drugs were administered ip. When the opioid drugs were administered into the fourth ventricle they produced a dose-related shortening of the latency of the low intensity thermally evoked tail avoidance reflex. (-)-Nicotine, when administered into the mid-fourth ventricle, produced analgesia in low doses and hyperalgesia in high doses. Naltrexone and mecamylamine, when administered into the fourth ventricle, produced a dose-related analgesia. Doses of naltrexone and mecamylamine which antagonize maximally hyperalgesic doses of (-)-nicotine and ethylketazocine did not produce analgesia; however, larger doses produced analgesia. These observations suggest that analgesic doses do not involve prototypic kappa opioidergic or nicotinic mechanisms. These data confirm the existence of a medullary hyperalgesic center which may have both mu and kappa opioidergic as well as nicotinic mechanisms. Furthermore, these data indicate that this medullary hyperalgesic mechanism may have spontaneous or evoked tone and provide an explanation for the analgesic action of naltrexone and mecamylamine.