The influence of centrally administered meperidine, normeperidine and pentazocine on the excitability of brain was studied by measuring the threshold for flurothyl-induced convulsions in rats. All three opioids are reported to lower seizure thresholds when given subcutaneously to rats in this test. Dose-and time-dependent changes in the seizure threshold occurred after intracerebroventricular injection of pentazocine (10-160 micrograms), meperidine (25-150 micrograms) and normeperidine (50-150 micrograms). Rapid increases in the seizure threshold were associated with pentazocine and meperidine, whereas a slowly developing decrease in the threshold was caused by normeperidine. Naloxone (10 mg/kg, s.c.) antagonized the anticonvulsant effect of meperidine (but not that of pentazocine) and enhanced the proconvulsant effect of normeperidine. Thebaine (25-150 micrograms), which had no marked influence on the seizure threshold when given intracerebroventricularly, lowered the threshold after subcutaneous injection of 12.5 and 25 mg/kg. This effect was not altered by injection of naloxone. These results show that centrally administered opioids can act on excitatory or inhibitory systems that regulate seizure mechanisms in the rat brain. Furthermore both naloxone-sensitive and naloxone-insensitive components are involved. Meperidine, pentazocine and thebaine have different actions on the seizure threshold after intracerebroventricular, as opposed to subcutaneous, administration. This work has, therefore, identified the route of administration as a critical variable in the effect of opioids on the seizure threshold in rats.

Animals↗

PubMed1984

The anticonvulsant effect of opioids and opioid peptides against maximal electroshock seizures in rats.

Opioids and opioid peptides influence the threshold to a seizure which is a model of petit mal epilepsy (Cowan, Geller and Adler, 1979). The present authors investigated representative opioid compounds in a model of a grand mal seizure, maximal electroshock (MES). Although all of the opioids and opioid peptides tested blocked tonic hindlimb extension, they divided into two groups, based on their ability to decrease the total length of the tonic component of the maximal electroshock seizure and their sensitivity to blockade by naloxone. The first group contained morphine, meperidine, methadone, ethylketocyclazocine (EK), D-ala2-met-enkephalinamide, D-ala2-leu5-enkephalin and beta-endorphin. The compounds in this group caused a decrease in the length of the tonic component that was dose-related, with the maximum decrease amounting to approx. 40%. The effect was blocked by the prior administration of 1 mg/kg of naloxone. The second group contained the partial agonists, pentazocine and cyclazocine. These opioids also caused a dose-related decrease in the length of the tonic component and, in the largest doses, the tonic component of the convulsion was completely blocked. Naloxone, in doses as large as 10 mg/kg, did not appreciably reverse the action of either drug.

Animals↗

PubMed1984

Intracerebroventricular vs. subcutaneous drug administration: apples and oranges?

For numerous reasons, the icv route is commonly used to administer endogenous opioid peptides and other newly discovered or synthesized substances and may often indicate whether the drug has actions on the brain. Effects are then routinely compared to the actions of prototypic agents given by some systemic route, such as sc or ip. Unfortunately, there is little appreciation that qualitative as well as quantitative differences can be seen when the same drug is administered by central as opposed to peripheral routes. Numerous factors undoubtedly contribute to the final effect. Whatever the explanation, failure to recognize that such differences may occur could result in incorrect conclusions as to the involvement of specific receptor types or subtypes.

Animals↗

PubMed1984

Homosexual men in London: lymphadenopathy, immune status, and Epstein-Barr virus infection.

By November 7, 1983, 24 cases of AIDS in the United Kingdom had been reported to the Communicable Disease Surveillance Centre. At the same time an increasing number of homosexual men with unexplained lymphadenopathy syndrome (LAS) have been seen in our department. Between December 1982 and July 1983, 14 homosexual men with LAS and 11 healthy homosexual men were studied. Patients with LAS had a high number of lifetime episodes of sexually transmitted diseases, a history of recent sexual activity in the United States (9 of 14), sexual contact with British AIDS patients or other persons with LAS (7 of 14), and hypergammaglobulinemia. Low T-helper/T-suppressor ratios (less than 0.8), due mainly to a decrease in T-helper cells, were found in both groups. Lymph node biopsies showed follicular hyperplasia and hypocellular pattern. All 25 patients studied had antibodies to Epstein-Barr virus capsid antigen (anti-VCA) and 11 had antibodies to early antigen (anti-EA); 13 of 17 were excreting the virus; and two showed no Epstein-Barr-virus-specific regression. Peripheral blood immunoglobulin-producing B-cells from six patients with hypergammaglobulinemia were negative for the Epstein-Barr virus nuclear antigen (EBNA). Five lymph node biopsies showed no EBNA-positive cells. Epstein-Barr virus reactivation is common in the patients with LAS and healthy homosexual men in London, but would not seem to be the cause of the polyclonal B-cell activation or lymphadenopathy.

Adult↗

PubMed1984

Contributions of neuropharmacology to understanding mechanisms of tolerance and dependence.

In summary, many of our once generally accepted ideas about tolerance and dependence have been revised as the result of neuropharmacological research. Included among these concepts are the following: Although tolerance and dependence are usually linked, they appear to be separable phenomena in some instances. Further exploration into each should be profitable. Although chronic administration of a drug is usually required to produce tolerance and dependence, even a single dose can result in these effects under certain conditions. That fact may provide us with clues as to the neuroadaptive changes occurring during the development of tolerance and dependence. A fruitful line of research emanates from the findings that tolerance may be pharmacokinetic or neuronal and that time of receptor occupancy appears to be a vital factor in neuronal tolerance. It is now known that tolerance does not develop equally to all actions of a drug and reverse tolerance (increased responsiveness) can occur. Further studies along these lines are needed to correct many false assumptions about this issue and to shed new light on the receptors and transmitter systems involved. We now accept the notion that a drug usually exerts effects on more than one receptor type or subtype. Consequently, the actions of drugs on the various receptors and the responses to receptor blockade promise to yield significant new knowledge about the mechanisms involved in tolerance and dependence to a wide variety of drugs. We have become increasingly aware of species differences and genetic determinants of responses to drugs of abuse, after both acute and chronic dosing. Other papers in this volume will focus on this topic.

Amphetamine↗

PubMed1983