The sensitivity to noxious heat in relation to brain and liver opioid glucuronidation in inbred strains of mice.

The glucuronidation of morphine and naloxone was demonstrated in the brain and liver in 2 inbred strains of mice, C57BL/6J (B6) and DBA/2J (D2) and their F1 hybrid generation. These strains showed a significant difference in latency of withdrawal in the tail-immersion test, the B6 strain being the most sensitive. The rate of naloxone glucuronidation in the brain was 5 times higher in the B6 than in the D2 strain. In the liver the UDP-glucuronosyl transferase (UDPGT) activity was slightly higher in the D2 strain. The naloxone- and morphine-3'-glucuronide (N3G, M3G) formation rate ratio was close to 1 in both the brain and liver in all except the B6 strain, where it was 2.6 in the brain. There was a correlation between formation rate of M3G and N3G (r = 0.65 brain and r = 0.73 liver). Our results indicate a common glucuronidation pathway for morphine and naloxone.

Human brain metabolism of morphine and naloxone.

The glucuronidation of morphine and naloxone was investigated in several regions of the human brain. Post-mortem brain tissue specimens were obtained from 19 patients 15 of whom had had cancer. With a few exceptions, all cancer patients had been treated with opiates during the terminal stage of their life. The glucuronide formation of morphine and naloxone was studied in vitro after incubation of the brain microsomal fraction with the substrate and uridine diphosphate glucuronic acid (UDPGA). The glucuronides were analyzed by high performance liquid chromatography. Glucuronidation of morphine and naloxone was catalyzed in 6 of the 19 investigated tissue specimens. The rate of formation of naloxone-3-glucuronide (N3G) exceeded that of the morphine-3-glucuronide (M3G). Morphine-6-glucuronide formation was found in only 2 specimens, in which the formation rate was 10% of the formation rate of M3G. When morphine and naloxone were present simultaneously at equal concentrations (3 mM), the N3G/M3G formation rate ratio increased compared to that when the 2 substrates were incubated one by one. Our findings are interesting from a clinical point of view since the pathways studied represent both bioactivation and inactivation steps in the metabolism of opioids.

Postoperative demand for analgesics in relation to individual levels of endorphins and substance P in cerebrospinal fluid.

Fourteen adult patients were allowed to self-administer small intravenous doses of pethidine to relieve postoperative pain. Thirteen of the patients obtained subjectively satisfactory analgesia while establishing steady-state levels of pethidine in plasma. The individual demand for pethidine was related to individual levels of fraction I endorphins and substance P-like immunoreactivity in the cerebrospinal fluid (CSF). There was a significant and inverse relationship between preoperative fraction I concentrations in CSF and the individual mean pethidine concentrations in plasma (P less than 0.05) and CSF (P less than 0.02) during self-administration. In the 24 h period encompassing surgery and postoperative self-administered analgesia, substance P decreased in 7 patients with calculated CSF pethidine great than 200 ng/ml, but remained virtually unchanged in 7 patients with calculated CSF pethidine less than 200 ng/ml. The results suggest a role for endorphins in the modulation of acute pain and are compatible with experimental evidence for an inhibitory effect of opiates on substance P release.

Endorphins in chronic pain. I. Differences in CSF endorphin levels between organic and psychogenic pain syndromes.

A series of 37 patients with chronic pain was investigated with regard to neurologic and psychiatric variables. Twenty of the patients were classified as having mainly organic (= somatogenic) pain syndromes while 17 patients were rather suffering from psychogenic pain syndromes. Samples of lumbar cerebrospinal fluid (CSF) were obtained from the patients and analyzed for the presence of opiate receptor-active material, here called endorphins. Patients classified as having mainly organic pain syndromes were found to have significantly lower endorphin levels than patients with predominantly psychogenic pain syndromes. In the total group of patients as well as in the two subgroups, there was a significant correlation between CSF endorphin levels and the depth of depressive symptomatology as reported by the patients. On the other hand, there was no correlation between CSF endorphin levels and extent of anxiety or motor retardation. It is concluded that CSF endorphins reflect central processes involved in chronic pain syndromes.