u-50488 and metkephamid

Despite significant opioid binding in the intermediolateral cell column, the effects of intrathecal injections of mu, delta, and kappa opioid agonists on the cardiovascular response to noxious stimulation have not been examined systematically. The pharmacology of intrathecally administered opioid agonists (mu, morphine, [D-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAGO); delta, metkephamid, [D-Ala2-D-Leu5]enkephalin (DADL), [D-Pen2,D-Pen5]enkephalin (DPDPE); kappa, U50488H and PD117,302) or agonist-antagonist (nalbuphine) on somatomotor (tail-flick) and cardiovascular changes (blood pressure and heart rate) evoked by immersing the tail in 53 degrees C water were examined in rats anesthetized with halothane (0.75%) and in which intrathecal catheters had been chronically implanted. Intrathecal administration of mu and delta, but not kappa agonists or agonist-antagonist produced a dose-dependent block of tail-flick and evoked cardiovascular responses with the order of activity being as follows: DAGO > metkephamid DADL > morphine > DPDPE >> nalbuphine = PD117,302 = U50488H = 0. These effects were reversed readily by the opioid antagonist naloxone. In addition, intrathecal administration of mu and delta but not kappa or agonist-antagonist had little effect on resting heart rate and blood pressure. These data indicate that the agonist occupancy of spinal mu and delta, but not kappa agonists can profoundly modulate the autonomic and somatomotor response evoked by high threshold thermal stimuli.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Anesthesia, Inhalation; Animals; Blood Pressure; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Methionine; Enkephalins; Halothane; Heart Rate; Hot Temperature; Injections, Spinal; Male; Morphine; Nalbuphine; Nociceptors; Pain Threshold; Pyrroles; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid; Reflex; Thiophenes

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Digestive System; Enkephalin, Leucine; Enkephalin, Methionine; Epilepsy; Kainic Acid; Male; Mice; Naloxone; Nervous System; Pyrrolidines; Receptors, Opioid

Possible modulatory effects of mu-, delta-, and kappa-receptor agonists on the concurrent adrenal secretion of catecholamines and met-enkephalin evoked by staged hemorrhage were examined in four groups of cats (n = 5 in each group) anesthetized with halothane (1 MAC). Group I received saline, group II received the mu-agonist sufentanil (25 micrograms/kg i.v., followed by a maintenance infusion), group III received the delta/mu agonist metkephamid (3 mg/kg i.v.), and group IV the kappa agonist U50488H (3.5 mg/kg i.v.). Samples for norepinephrine, epinephrine, dopamine, and met-enkephalin were taken simultaneously from the adrenal vein, femoral vein, and femoral artery at baseline, after drug administration, and after induction of 25% and 50% hemorrhage. In cats receiving saline, 25% hemorrhage resulted in a significant decline in mean arterial blood pressure (MABP) and no change in adrenal secretion. Fifty percent hemorrhage evoked no significant further fall in MABP, but led to prominent increases in adrenal vein hormone levels (norepinephrine, 30-fold; dopamine, 14-fold; and epinephrine, ten-fold) as compared to post-saline values. During the pre-hemorrhage baseline state, administration of sufentanil evoked a significant six- to 20-fold rise in adrenal vein catecholamine and met-enkephalin levels, whereas the administration of metkephamid and U50488H produced no change in adrenal secretion and a decrease in MABP. After 25% and 50% hemorrhage, there was no difference in adrenal vein hormone levels in cats receiving the mu-, delta-, or kappa-agonists compared to those receiving saline. No differences were observed in the different treatment groups with regard to the proportional levels of catecholamines and met-enkephalin in the adrenal vein during the course of the experiment. The authors conclude that opioids are not involved in the regulation of the secretory adrenal medullary response evoked by hemorrhage, and that the systems involved in mediating these cardiovascular reflexes differ pharmacologically from those systems mediating the autonomic response evoked by pain.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenal Medulla; Anesthesia, Inhalation; Animals; Catecholamines; Cats; Endorphins; Enkephalin, Methionine; Fentanyl; Halothane; Hemorrhage; Pyrrolidines; Receptors, Opioid; Sufentanil