Gayle Giboney Page

Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity

Stress and surgery have been suggested to compromise host resistance to infectious and malignant diseases in experimental and clinical settings. Because stress affects numerous physiological systems, the role of the immune system in mediating such effects is unclear. In the current study, we assessed the degree to which stress‐induced alterations in natural killer (NK) cell activity underlie increased susceptibility to tumor development in F344 rats. Two stress paradigms were used: forced swim and abdominal surgery. Host resistance to tumor development was studied using 3 tumor models syngeneic to inbred F344 rats: CRNK‐16 leukemia and the MADB106 mammary adenocarcinoma, both sensitive to NK activity, and the NK‐insensitive C4047 colon cancer. Swim stress increased CRNK‐16‐associated mortality and metastatic development of MADB106 but not metastasis of C4047 cells. In both stress paradigms, stress suppressed NK activity (NKA) for a duration that paralleled its metastasis‐enhancing effects on the MADB106 tumor. In vivo depletion of large granular lymphocyte/NK cells abolished the metastasis‐enhancing effects of swim stress but not of surgical stress. Our findings indicate that stress‐induced suppression of NKA is sufficient to cause enhanced tumor development. Under certain stressful conditions, suppression of NKA is the primary mediator of the tumor‐enhancing effects of stress, while under other conditions, additional factors play a significant role. Clinical circumstances in which surgical stress may induce enhanced metastatic growth are discussed. Int. J. Cancer 80:880–888, 1999.

Morphine attenuates surgery-induced enhancement of metastatic colonization in rats

&NA; Painful Stressors such as surgery have been shown both to suppress immune function and to enhance tumor development. Whether the immune system mediates the tumor‐enhancing effects of surgery remains unclear. Moreover, the role of postoperative pain has been largely ignored in such studies. To explore these issues, we used the MADB106 tumor, a mammary adenocarcinoma syngeneic to the subjects of this study (Fischer 344 rats) and known to be sensitive to natural killer (NK) cell activity. We found that surgery enhanced metastatic colonization and that this tumor‐enhancing effect occurred only during the time in which the MADB106 tumor is sensitive to NK control. These results support the hypothesis that suppression of NK cell activity mediates the surgery‐induced enhancement of metastatic colonization. Further, we found that an analgesic dose of morphine blocked the surgery‐induced increase in metastasis without affecting metastasis in unoperated animals. These findings suggest that postoperative pain is a critical factor in promoting metastatic spread. If a similar relationship between pain and metastasis occurs in humans, then pain control must be considered a vital component of postoperative care.

Neonatal testosterone exposure influences neurochemistry of non-opioid swim stress-induced analgesia in adult mice

&NA; The effects of neonatal hormone manipulations on swim stress‐induced analgesia (SSIA) magnitude and neurochemical quality were examined in Swiss‐Webster mice of both sexes. Previous research has indicated that non‐opioid SSIA mechanisms in adult Swiss‐Webster mice are sexually dimorphic. Male mice exhibit non‐opioid SSIA following a 3‐min swim in cold (15°C) water that is antagonized by the non‐competitive NMDA antagonist MK‐801 (dizocilpine; 0.075 mg/kg), whereas female mice do not display NMDA‐mediated analgesia in the presence of estrogen. Since male and female mice show equipotent magnitudes of SSIA, it was concluded that female mice display a neurochemically distinct, estrogen‐dependent SSIA mechanism specific to their gender. In the present study, female mice exposed to testosterone during the neonatal period display NMDA‐mediated analgesia even in the presence of estrogen in adulthood. Thus, expression of the female‐specific, estrogen‐dependent SSIA mechanism previously described may be dependent on the absence of testosterone during early ontogeny.

The Immune-Suppressive Nature of Pain

OBJECTIVESnTo review evidence that the immune system plays a role in controlling the spread of cancer and findings that perioperative pain relief improves immune status and health outcomes.nnnDATA SOURCESnResearch studies and review articles pertaining to immunity, immune function, stress, and immune-suppressive nature of pain.nnnCONCLUSIONSnPain not only results in suffering but is a pathogen itself, capable of facilitating the progression of metastatic disease. Adequate pain relief decreases these risks.nnnIMPLICATIONS FOR NURSING PRACTICEnAdequate pain relief is not only a primary concern in caring for individuals in pain but may be a matter of physiologic necessity as further studies reveal the immune-suppressive nature of pain.

Increased susceptibility to metastasis during pro-oestrus/oestrus in rats: Possible role of oestradiol and natural killer cells

It has been suggested that tumour development and immunocompetence are affected by the menstrual and the oestrous cycle, and sex hormones have been shown to modulate lymphokine production, neuroendocrine activity and immunity. In this study, we assessed natural killer cell activity and host susceptibility to metastasis during the oestrous cycle in the Fischer 344 inbred rat strain. Females were inoculated intravenously with MADB106 tumour cells, a syngeneic mammary adenocarcinoma cell line that metastasises only to the lungs. The susceptibility to metastatic development of this tumour was found to be significantly higher during pro-oestrus and oestrus than during metoestrus and dioestrus. Two days of exposure to oestradiol benzoate caused similar effects in ovariectomised females, and a single administration of progesterone reduced this effect of oestradiol to a statistically non-significant level. The tumour was found to be negative for oestradiol receptors, and its in vitro proliferation rate was not affected by oestradiol or progesterone, suggesting that the effects of sex hormones on the metastatic process are not attributable to a direct effect on tumour cells. Because the metastatic process of MADB106 tumour cells is known, and confirmed here, to be highly controlled by large granular lymphocyte/natural killer (LGL/NK) cell activity, we assessed their role in mediating the effects of the oestrous cycle. The number and activity levels of circulating blood LG/NK cells (NKR-PI+ bright) were studied. Findings indicated oestrous-dependent alterations in the number of LGL/NK cells and suggested a diminished NK activity per LGL/NK cell during pro-oestrus/ oestrus, the same phases that were characterised by higher susceptibility to metastatic development. These findings provide the first empirical evidence for a causal relationship between a short-term exposure to elevated oestradiol/low progesterone levels and decreased resistance to tumour metastasis, and it is hypothesised that an alteration in LGL/NK cell activity underlies these effects. Homologies and relevance to clinical phenomena are discussed.

N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 blocks non-opioid stress-induced analgesia. I, Comparison of opiate receptor-deficient and opiate receptor-rich strains of mice

The effects of the specific N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 (0.075 mg/kg), and the specific opiate receptor antagonist naloxone (10 mg/kg), on swim stress-induced analgesia (SSIA) were studied in opiate receptor-deficient (CXBK) and opiate receptor-rich (CXBH) mice. Animals were subjected to forced swimming, and analgesia was assessed using the hot-plate test. In CXBK mice SSIA was blocked by MK-801 but was completely insensitive to naloxone. In CXBH mice SSIA was partially attenuated both by naloxone and MK-801, and it was nearly abolished by a combination of these drugs. Morphine analgesia (10 mg/kg) was abolished by naloxone but completely unaffected by MK-801 in CXBH mice. These findings suggest that the NMDA receptor is critically involved in the non-opioid component of SSIA.

Increased surgery-induced metastasis and suppressed natural killer cell activity during proestrus/estrus in rats

We have previously reported sex- and estrous-related differences in hostresistance to the metastatic development of a mammary adenocarcinoma cellline, MADB106, in the Fischer 344 (F344) rat. In other studies, we foundthat surgery suppressed natural killer (NK) cell activity and increased theNK-sensitive metastatic development of MADB106 tumor cells. The currentstudy was designed to explore whether sex or estrous phase at the time ofsurgery impacts the degree of such deleterious effects of surgery. Suchestrous effects could be related to an ongoing clinical debate regarding theimportance of the timing of breast cancer surgery with the menstrual cyclein premenopausal women. Mature F344 males and cycling females underwenteither experimental laparotomy with halothane anesthesia, halothaneanesthesia alone, or were untreated. Five hours after surgery, animalseither were injected with radiolabeled MADB106 tumor cells and assessed forlung tumor cell retention 12 hours later, or underwent blood withdrawal forin vitro assessment of NK cell activity. MADB106 tumor cells metastasizeonly to the lungs, and lung tumor cell retention is: a) an early indicatorof the number of metastases that would develop weeks later, and b) highlysensitive to in vivo levels of NK activity. This mammary adenocarcinoma cellline is syngeneic to the inbred F344 strain of rats used in our studies,thus constituting a model for breast cancer metastasis. The resultsindicated that sex, estrous phase, and surgery interacted in their effectson NK cell activity and tumor metastasis. MADB106 lung tumor cell retentionwas increased by surgery in both sexes (2- to 3-fold) compared to theanesthesia only and control groups. This increase, however, wassignificantly greater in proestrus/estrus (P/E) females than inmetestrus/diestrus (M/D) females. Among the control animals, females in P/Eexhibited significantly less NK cytotoxic activity compared to the males,and the NK activity exhibited by females in M/D was between these twogroups. Surgery suppressed NK cytotoxic activity to a similar level in allgroups. Possible implications of these findings for the surgical care ofwomen with breast cancer are discussed.

The medical necessity of adequate pain management

The experience of pain is not a benign one. This article reviews evidence that painful experiences, including those associated with surgery, result in a perturbation of the neuroendocrine system, leading to immune suppression and the promotion of pathological processes that are normally resisted by the immune system, such as infection and cancer. Evidence that natural killer (NK) cells control the development of metastasis provides a link between immune function and health outcomes. Using an NK-sensitive tumor model in rats, it was recently shown that the pre- and postoperative administration of an analgesic dose of morphine attenuated the observed surgery-induced increase in metastasis, suggesting that pain relief enabled the host to resist this life-threatening consequence of surgery. Further, other studies have shown that whereas rats become rapidly tolerant to the immune-suppressive and tumor-enhancing effects of morphine, no such tolerance develops to daily exposure to painful footshock stress. Taken together, these findings affirm both the benefits and relative safety of morphine contrasted with the pathogenic nature of pain in this context, thus suggesting that the adequate management of pain must become a vital aspect of health care.

Chronic pain and the child with juvenile rheumatoid arthritis.

This article presents a summary of nursing issues concerning the assessment and management of pain in children with juvenile rheumatoid arthritis (JRA). Following a brief description of the difference between acute and chronic pain and a description of JRA, the developmental issues relating to pain assessment in this population are discussed. Three pain assessment tool alternatives are presented. Finally, current strategies for pain relief and treatment of children with JRA are presented.

Balancing the risks of pain with the risks of pain-relieving drugs

T hanks to Drs. Weber, Shavit and Beilin, and Maier and Watkins for the thought-provoking commentaries and the opportunity to further explore several issues arising from the Focus article. The commentaries provide both motivation and rationale to continue investigating the impact of providing pain relief on the immune and metastatic consequences of undergoing and recovering from surgery. Clearly, the findings most directly illustrating the immune and metastatic benefits of morphine administration are preliminary at best. If we in health care are to view the management of pain as a medical necessity, we must have substantially more information to balance the physiologic risks of pharmacologic interventions with the physiologic risks of inadequately managed pain.