The effects of different 4-aminopyridine and morphine combinations on the intensity of morphine abstinence

Abstract

The glutamatergic system is deeply involved in the development of opiate dependence and in the manifestation of opiate abstinence syndrome. In this study the effect of the increase in the endogenous glutamate (GLU) release due to 4-aminopyridine (4-AP), a potassium channel blocker, during the development of morphine (M) physical dependence and during the naloxone (NL)-precipitated abstinence syndrome was investigated. For the development of physical dependence M was intraperitoneally (i.p.) injected for 9 days 105 min following i.p. saline administration to a group of rats. In the first 3 days the dose of M was 10 mg kg−1. In the second 3 days the initial dose was doubled (20 mg kg−1) and in the last 3 days the dose of M was raised to 40 mg kg−1. On day 10, the rats were divided into three groups at random and these three groups were i.p. given saline 105 min before 80 mg kg−1M, 2 mg kg−14-AP 105 min after 80 mg kg−1M, and 80 mg kg−1M 105 min before 2 mg kg−14-AP, respectively. In a second group of rats, the rats were i.p. given 2 mg kg−14-AP 105 min prior to M administration, which was increased every 3 days (10 mg kg−1, 20 mg kg−1, 40 mg kg−1). On day 10, the rats were divided into two groups whose first injection was saline and 2 mg kg−14-AP, respectively. The second injections of both groups after an interval of 105 min following the first one contained 80 mg kg−1M. In contrast, one group of rats received only i.p. saline at every other injection time (the control group). Furthermore, another group of rats was i.p. administered 2 mg kg−14-AP once a day, as the first injection. At the second injection time they were i.p. given saline. After a period of 15 min following the last administration on day 10, the rats belonging to all groups were i.p. injected with 2 mg kg−1NL and immediately placed in a metal cage. Body weight loss (g), teeth chattering, rearing, wet-dog shaking, grooming, and jumping were determined or counted for 15 min. Penile erection, defecation, and diarrhoea were separately scored with one point for every individual occurrence, and the total score was named ‘total number of others’. The administration of 4-AP before M appeared to intensify the development of dependence, and was most probably due to the Ca2+-induced inactivation of NMDA receptors as a result of excess release of GLU when the 4-AP took effect. The inactivation of NMDA receptors should have acted as a transient blockade of the receptors during the chronic administration period, and as well as after a single administration on day 10 before M injection and before abstinence. The intensification of the abstinence syndrome may be dependent on the excessive GLU released by 4-AP.