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 produced an immediate increase in blood pressure. Heart rate increased in most rats just after naloxone injection; however, the responses were transient, not lasting more than about 4 min after injection. Naloxone-precipitated behavioral changes were dominated by the appearance of body shakes and escape attempts that were strongly expressed during the first 10 min after naloxone. Pretreatment of morphine-dependent rats with an intrathecal injection of 100 nmol of the neurokinin-1 receptor antagonist CP-99994 significantly inhibited the magnitude and shortened the duration of the pressor response to naloxone. CP-99994 did ot reduce the expression of the associated withdrawal behaviors. Substance P significantly reversed the inhibitory effects of CP-99994 on the expression of the withdrawal-associated pressor response. Intrathecal pretreatment with CP-99994 also produced a dose-dependent inhibition of the expression of the pressor response to local spinal (intrathecal) injection of naloxone (60 micrograms) in morphine dependent rats without significant alteration of the expression of withdrawal-associated behaviors. These results indicate that spinal neurokinin-1 receptors mediate some of the cardiovascular signs of morphine withdrawal and suggest the possibility of developing a novel class of antiopiate withdrawal agents.