Nicholas P. Plotnikoff

Enkephalins as immunomodulators

The protective effects of methionine enkephalin as well as leucine enkephalin were studied in BDF1 mice inoculated with 1 X 10(4) and 1 X 10(2) cells of L1210 murine leukemia. Significant increases in number of survivors were observed in mice treated with enkephalins. Methionine enkephalin in the presence of PHA was found to stimulate lymphocyte blastogenesis at concentrations of 1 mg/ml to 10(-8) mg/ml. In the case of leucine enkephalin, concentrations of 1 mg/ml to 10(-10) mg/ml stimulated blastogenesis. Stimulation of blastogenesis was seen at PHA dilutions of 1:100, 1:250, 1:750, with both methionine enkephalin and leucine enkephalin. The results are discussed in terms of immunomodulation. It is proposed that endogenous enkephalins play a neuroendocrine role between the central nervous system and the immune system and are direct immunostimulants.

Neuroimmunomodulation with enkephalins: Enhancement of human natural killer (NK) cell activity in vitro

To further define the effects of enkephalins on immune function, the effect of methionine-enkephalin and leucine-enkephalin on natural killer cell (NK) activity in isolated human peripheral blood lymphocytes was investigated. Incubation of lymphocytes with either enkephalin resulted in significant increases in natural killer cell activity. At effector:target cell ratios of 11:1 methionine-enkephalin significantly (P less than 0.05) enhanced NK activity at dilutions of 10(-6), 10(-8), 10(-10), and 10(-14) mg/ml, while leucine-enkephalin significantly (P less than 0.05) enhanced NK activity at dilutions of 10(-4), 10(-6), 10(-8), 10(-10), and 10(-14) mg/ml. Cells from individuals with low NK activity showed greater percentage increases in NK activity following enkephalin than did cells from individuals with high NK activity.

Enkephalins—Enhancement of active T-cell rosettes from lymphoma patients

Methionine enkephalin was found to increase significantly the active T-cell rosettes from lymphoma patients. In sharp contrast, the leucine enkephalin was observed to increase active rosettes only at a single low concentration. Neither enkephalin significantly altered the total T-cell rosettes. It is suggested that methionine enkephalin could have a significant influence in enhancing cell-mediated immunity and T-cell function, particularly in lymphoma patients.

Enkephalins—Enhancement of active T-cell rosettes from normal volunteers

Both methionine enkephalin and leucine enkephalin were found to increase significantly the active T-cell rosettes of normal volunteers. Neither enkephalin altered total T-cell rosettes. It is proposed that the endogenous enkephalins (methionine as well as leucine) have a role in cell-mediated immunity and T-cell function.

Immunologic Properties of Methionine‐Enkephalin, and Therapeutic Implications in AIDS, ARC, and Cancer

These past years have represented a crossroads of several new avenues of research. Among these areas, study of the connections between the three major systemsthe central nervous system, the endocrine system and the immune system-raises new hope for a better understanding of human physiology and pathology. One of the links between these three systems is that of the endogenous opioid peptides like the enkephalins and the endorphins. The endogenous opioid peptides play a major role as chemical messengers of inhibitory signaling systems such as the opening of K+ channels and the depression of transmitter release. These peptides are essentially released after such various stimuli as shock and stress. Enkephalins are small peptides composed of five amino acids, whereas endorphins are composed of 16 to 3 1 amino acids. Although the structure of methionine-enkephalin (Met-Enk) is similar to the sequence of the first five amino acids of the endorphins, endorphins and enkephalins originate from different precursors (propiomelanocortin composed of 264 amino acids for the endorphins and proenkephalin A composed of 236 amino acids for the enkephalins). The structure of Met-Enk is Tyr-Gly-Gly-PheMet, whereas the structure of leucine-enkephalin is slightly different, Tyr-Gly-GlyAle-Leu. The enkephalins can be synthesized chemically. Met-Enk possesses a molecular weight of 573.65 and its purity is assessed by HPLC (Union Chimique Belge;

Enkephalins: Mediators of Stress-Induced Immunomodulation

It is well known that environmental stress can influence the immune response and tumor growth (1). Although stress has usually been associated with detrimental effects on the host, under certain experimental conditions of timing and duration of stressful stimuli. immunoenhancement and inhibition of tumor growth can result (1,2.3,4). In addition, stress brings about numerous biochemical changes including the release of neurotransmitters, corticosteroids, and other hormones that can have various effects on the immune system and which may be benificial or detrimental to the host (5,6,7).

Neuroimmunomodulation with enkephalins: Effects on thymus and spleen weights in mice

The subcutaneous injection of either methionine-enkephalin or leucine-enkephalin in BDF1 mice resulted in a significant increase in thymus weight and a significant decrease in spleen weight. This study further supports earlier findings that the enkephalins are neuroimmunomodulators.

Enhancement of Host Resistance to Viral and Tumor Challenge by Treatment with Methionine‐Enkephalin

Host resistance to disease is dependent upon a number of factors. Recent evidence indicates that natural killer (NK) cells play an important role in resistance to both neoplastic and virally induced disease. Treatment of C57Bl/6 mice with methionine-enkephalin (1, 3, 10, or 30 mg/kg body weight) results in significant increases in NK activity of splenic lymphocytes 20 hours after injection of the enkephalin. Enkephalin treatment also enhances host resistance. The short-term survival of A/J female mice after HSV-2 infection was significantly increased by daily subcutaneous injections (3 mg/kg body weight) of methionine-enkephalin. Similarly, daily doses of 50 micrograms of methionine-enkephalin for 7 to 14 days inhibit the local subcutaneous tumor growth of B15 melanoma in C57Bl/6 mice.

Methionine Enkephalin: Immunomodulator in Normal Volunteers (in Vivo)

The enkephalin, methionine enkephalin (met-enkephalin) was originally discovered to be one of the endogenous ligands for morphine receptors (Hughes et al., 1975; Simontov and Snyder, 1976). However, Plotnikoff et al., (1976) discovered anti-depressant, anti-anxiety, and anti-convulsant effects of the enkephalins, identifying a much broader spectrum of pharmacological effects than originally anticipated.

Effect of methionine-enkephalin plus ZnCl2 on active T cell rosettes

Methionine-enkephalin (Met-Enk) and ZnCl2 in combination enhances active T cell rosette formation of human peripheral blood lymphocytes to a greater degree than either of the agents used separately. Enhancement of rosette formation by Met-Enk plus ZnCl2 was not inhibited by the opiate receptor antagonist naloxone but was completely blocked by the zinc chelator 1,10-phenanthroline. The results suggest a relationship between zinc and Met-Enk and that zinc may be a modulator of enkephalin binding and function in the immune system as well as the nervous system.