When a post-surgery patient is wheeled out of the operating room and into the recovery room, the last thing he or she needs is a body blow to the immune system. Ditto, a late-stage cancer sufferer.
In both situations, a frequent cardinal feature is intractable, unbearable pain. As lesser analgesics fail to relieve the agony, morphine - the opioid painkiller of last resort - takes over.
Now, a brief research report in today's Nature, dated Jan. 21, 1999, suggests that morphine has a significant side effect - suppressing the immune system. Its title, hinting at the mechanism involved, reads "Fas-mediated cell death promoted by opioids."
The article's senior author is immunologist Yufang Shi, a principal scientist at the American Red Cross's Holland Laboratory for Biomedical Sciences in Rockville, Md. Since the 1980s, he has researched the mechanism of lymphocyte cell death, now called apoptosis.
"Our goal is very broad," Shi told BioWorld Today. "It's to understand the tolerance mechanism of the immune system. It's well known," he added, "that opioids could suppress the immune system. So we were thinking, 'What is really happening?' Is this really due to making the immune cell die?"
He continued: "Because opioids have been used normally in the patient and abnormally in the addict, and knowing morphine's association with immunosuppression, we decided to do the experiments we describe in Nature."
Those experiments found, in vitro and in vivo, that morphine could induce the expression of the Fas molecule, which causes immune cells to die. "In our in vitro system," Shi recounted, "Fas alone did not cause cell suicide, because Fas-mediated apoptosis also needs a Fas ligand (FasL). But in vivo we could see that it killed some lymphocytes."
When he and his co-authors gave morphine to mice, they found the animals' splenocytes (mature immune-system lymphocytes) dropped in number by 30 percent within 24 hours. Adding a Fas-FasL fusion protein to the opioid dosage prevented that splenocyte loss, whereas normal mouse serum did not.
Naloxone, a chemical that avidly blocks the brain's opioid receptors, also saved splenocytes from extinction. This pathway, Shi proposed, "contributes to the immunosuppressive effects of morphine."
Moreover, morphine induced Fas expression in spleen, heart and lung within 12 hours.
Fas is a cell-surface protein that transmits its apoptosis message to the cell's nucleus. Its ligand, FasL, is a membrane protein that executes that cell death by binding to Fas. Activated T lymphocytes express FasL, which then implements cytotoxic killer T-cell action. (See BioWorld Today, June 4, 1997, p. 1.)
"So our overall finding in this Nature paper," Shi said, "is that opioid could make immune cells express Fas, which sensitizes cells to undergo apoptosis, when activated by FasL.
"This is very interesting," he went on, "probably a new way to understand the immune system. We really want to know now, what is the mechanism? Fas expression does not necessarily make the cell die. Rather, a Fas signal makes it more susceptible to apoptosis."
Human Brain Makes Its Own Morphine
Another facet of the mechanism he and his lab are now exploring is the body's endogenous opioid receptor and its ligand, endorphin, long acclaimed as "the brain's own morphine." (See BioWorld Today, Dec. 1, 1998, p. 1.)
"Because our bodies produce this endogenous opioid," Shi continued, "I really wanted to know, is this a mechanism to communicate between the immune system and the neuronal system? And more importantly, how does it really work? Why, throughout evolution, have humans needed to suppress their immune system in such emergency states as pain or other stressful situations, and get an acute increase of endorphin in the brain?"
Shi is not yet ready to articulate his still-forming hypothesis as to why, then, should opioids suppress the immune system. But he does suggest some possible clinical applications.
"Because opioids have been widely prescribed as a painkiller, how could we use just its analgesic mechanism, but get rid of the apoptosis mechanism?" He envisages such decoupling as "using different pathways for Fas ligand, or in combination with apoptosis-prevention agents. Either block apoptosis directly, or directly inhibit the Fas-Fas ligand interaction."
Efforts to design or discover anti-apoptotic drugs are under way, he pointed out, but "new ones are not in clinical practice yet. Lots of things inhibit apoptosis, in different systems through different ways. I'm sure that in the future, scientists will define something that can specifically inhibit this type of programmed cell death."
In view of the postulated negative effect of morphine on the body's immune defenses, shouldn't narcotics addicts be particularly subject to infections?
"Say you have a little bit of endorphin," Shi replied. "Probably - and I'm not promoting drugs here - if you don't use too much, maybe it's good for your immune system. But most times, when we give endorphin exogenously, or probably when an addict makes it endogenously, there is too much. And too much is not good."
Do Infections Ensue In Man Or Beast?
On this score, Shi cited "reports showing that in HIV-infected drug addicts, the latent period between HIV-positive and full-blown AIDS is shorter. We don't know whether this effect contributes to that or not, so it could be another good direction of study in the future."
The co-authors' in vivo mouse experiments stopped short of determining whether the decline in their spleen cells led the animals to develop infections. "You know," he pointed out, "those kinds of infections are very difficult for mice to get. Some animals don't have any lymphocytes.
"We did the experiments for a very short time," he observed. "To proceed to a longer treatment regimen, we would have to get a different animal protocol."
He intends to do so, but first "we will probably use mice to see the dynamic lymphocyte changes that morphine effects in them. We gave only two doses, maximum, for this study, but if we continue to administer it for a longer period, we want to see what is going to happen.
"After we get those results," he added, "maybe we will look at some bacterial or viral infection model.
"I don't want to speculate too much," Shi concluded, "but in the future maybe we can relate the addiction mechanism, which produces apoptosis, to some cancers. At our present early stage, I think we've got more questions than answers." n