EFFECT OF INTRATHECAL PRETREATMENT WITH THE NEUROKININ RECEPTOR ANTAGONIST CP-99994 ON THE EXPRESSION OF NALOXONE-PRECIPITATED MORPHINE-WITHDRAWAL SYMPTOMS

In morphine-dependent rats pretreated with an intrathecal injection of saline (vehicle), intraarterial injection of 0.5 mg/kg of naloxone pr oduced an immediate increase in blood pressure, Heart rate increased i n most rats just after naloxone injection; however, the responses were transient, not lasting more than about 4 min after injection, Naloxon e-precipitated behavioral changes were dominated by the appearance of body shakes and escape attempts that were strongly expressed during th e first 10 min after naloxone. Pretreatment of morphine-dependent rats with an intrathecal injection of 100 nmol of the neurokinin-1 recepto r antagonist CP-99994 significantly inhibited the magnitude and shorte ned the duration of the presser response to naloxone. CP-99994 did not reduce the expression of the associated withdrawal behaviors, Substan ce P significantly reversed the inhibitory effects of CP-99994 on the expression of the withdrawal-associated presser response, Intrathecal pretreatment with CP-99994 also produced a dose-dependent inhibition o f the expression of the presser response to local spinal (intrathecal) injection of naloxone (60 mu g) in morphine dependent rats without si gnificant alteration of the expression of withdrawal-associated behavi ors, These results indicate that spinal neurokinin-1 receptors mediate some of the cardiovascular signs of morphine withdrawal and suggest t he possibility of developing a novel class of antiopiate withdrawal ag ents. (C) 1997 Elsevier Science Inc.