| Opioids, such as morphine, and stress are both known to adversely affect immune and neuroendocrine functioning, with both generally resulting in suppression of mitogenic T lymphocyte responses and elevation of stress hormones. However, the extent to which opioids and stress systems overlap, especially in terms of modulation of immune responses, has not been fully elucidated. In particular, it has been noted that animals treated chronically with morphine (10-40 mg/kg, b.i.d, 8 days) develop an apparent immunologic tolerance to the suppressive effects of an analgesic dose of morphine (10 mg/kg), however, these same animals are highly immunologically vulnerable to novel stress challenge. The studies described in this dissertation, therefore, examine this heightened immune sensitivity following chronic morphine administration and endeavor to determine mechanisms leading to this vulnerability.; To examine opioid-mediated stress pathways involved in immunomodulation, acute neurogenic stressors, water stress and restraint, were compared to immune stressors lipopolysaccharide (LPS) and interleukin-1beta (IL-1beta) in naive animals as to their T lymphocyte proliferation responses, and plasma IL-6 and corticosterone levels. Pretreatment with the opioid antagonist naltrexone (10 mg/kg, s.c.) exacerbated the negative effects of severe stressors and attenuated the effects of mild stressors, however, the actual opioid-mediated stress pathways utilized by these stressors could not be determined.; As repetitive injections with morphine are considered a stressor, repeatedly restraint stressed (30-120 min/day, b.i.d., 8 days) animals were compared to chronic morphine rats in terms of their responses to LPS challenge. Both chronic morphine and repeatedly stressed rats were highly sensitive to LPS challenge and displayed significant decreases in proliferation and increases in plasma corticosterone. Chronic morphine animals were also vulnerable to challenge with IL-1beta. Moreover, chronic morphine animals exhibited aberrant LPS-induced central IL-1beta and IL-10 production, whereas no alterations in central IL-1beta production were observed in repeatedly stressed rats.; Furthermore, studies revealed that chronic morphine-induced alterations in brain-to-immune stress pathways-hypothalamic pituitary adrenal (HPA) axis and autonomic nervous system (ANS)-were primarily responsible for the immune vulnerability of these animals. Finally, dysregulation of central cytokine production also may be involved in the immune sensitivity, as central administration of exogenous IL-10 negated IL-1beta-induced immunosuppression. |
