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VOL. 75 (3), 389-418, 2009 CENTRAL AND PERIPHERAL ENDOGENOUS MORPHINE

The injection of lipopolysaccharide (LPS, an integral component
of the cell walls of Gram-negative bacteria) into rats is used to study
sepsis. In this system, LPS is known to induce an increase in the
concentration of endogenous morphine in the adrenal glands (76) and
brain (77). Other types of stress (like starvation) also induce rises in
morphine levels in the spinal cord (76).

Morphine is known to be able to have immunosuppressant
activity via various distinct mechanisms (117):

(i) direct action on monocytes, macrophages and granulocytes:
by inducing nitrogen oxide [NO (22)] and thereby inhibiting
the production of pro-inflammatory cytokines as well as
chemotaxis and phagocytosis (116). On the other hand, the
binding of morphine to µ receptors on endothelial cells
also induces NO production and inhibits the expression of
certain adhesion molecules involved in the recruitment of
immune cells to sites of infection and inflammation;

(ii) activation of the hypothalamic-pituitary-adrenal axis (HPA)
and release of immunosuppressive glucocorticoids (119);

(iii) inhibition of the differentiation of stem cells into lympho-
cytes, and inhibition of T lymphocyte multiplication (120);

(iv) inhibition of the cytolytic activity of NK cells (119-121):
this has been observed after the direct injection of morphine
into the cerebrospinal fluid, suggesting that the effect is
mediated in the central nervous system.

The release of morphine in the blood could represent a physiolo-
gical mechanism designed to mitigate over-exuberant inflammatory
reactions. Morphine is also known to induce analgesia so it could, if
present at high enough levels in the blood (113, 114) or brain (77)
at times of stress, modulate the activity of peripheral nociceptors.

3. CONCLUSION

In summary, numerous studies have established a role for
morphine as an endogenous signalling molecule. Thus, endogenous
morphine appears to be both a neurotransmitter and endocrine

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