Sub-chronic exposure to opiates in the rat: effects on brain levels of substance P and calcitonin gene-related peptide during dependence and withdrawal.

Substance P (SP) and calcitonin gene-related peptide (CGRP) are putative transmitters in the central and peripheral (sensory) nervous systems. In this study, we examined the effects of dependence on and withdrawal from morphine and methadone on brain SP and CGRP content. Female Long Evans rats (70-100 g) were provided with plain drinking water or solutions containing opiate. No choice of drinking fluid was allowed. The maintenance level of each opiate (0.8 and 0.4 mg/ml for morphine and methadone, respectively) was continued for 4 days. Following an injection with naloxone (10 mg/kg i.p.) or saline, animals were decapitated 0, 20, or 60 min later and regional brain peptide content was measured by specific radioimmunoassays. SP and CGRP content in opiate-maintained and naive animals were similar following saline injection. However, following naloxone injection in morphine-maintained animals, SP content was elevated in the hypothalamus and midbrain at 20 min, but by 60 min was no longer distinguishable from basal (0 min) level. CGRP content was increased in the medulla oblongata and followed a comparable time course but, unlike SP, was not altered in the hypothalamus or midbrain. No alterations were observed in methadone-maintained animals. These results correlated with the peak of the behavioral morphine withdrawal syndrome and were consistent with the comparatively milder abstinence encountered in methadone medication.