Opioid receptor-mediated action in the
central nervous system (CNS) has been consistently shown to trigger changes in the hypothalamic-pituitary-adrenal (HPA) axis and the
sympathetic nervous system (SNS) and suppress a variety of parameters of
immune function in investigator-delivered paradigms. Overwhelming evidence supports the concept that the CNS undergoes numerous and complex
neuronal adaptive changes in addicts, and in animal models of
heroin addiction as a result of the training of
drug stimuli to serve as reinforcers, altering the function of individual
neurons and the larger
neural circuits within which the
neurons operate. Taken together, these advances suggest that since
plastic neuronal changes occur in
drug addiction and related animal model paradigms, profiles of
neuroendocrine and
immune function would differ in a rat model of
heroin self-administration compared to passive infusion of
drug. Self-administration of
heroin induces
neuronal circuitry adaptations in specific
brain regions that may be related to alterations in
neuroendocrine and
T lymphocyte function also observed. Animals self-administering (SA)
heroin exhibit increased mu-opioid
receptor agonist ([D-Ala2, N-Me-Phe4, Gly5-ol]-
enkephalin (
DAMGO))-stimulated guanosine-5'-O-(gamma-thio)-triphosphate ([(35)S]
GTPgammaS) binding in the
anterior hypothalamus (50% and 33%) and rostral medial
thalamus (33% and 36%) compared with control animals receiving identical non-contingent injections of yoked-heroin (YH) or yoked-saline (YS), respectively. No changes in agonist-stimulated
G-protein sensitization were observed in 14 other
brain regions studied. No changes in mu-opioid receptor
density, ((3)H-DAMGO binding) were seen in all
brain regions examined. The
neuronal changes in SA animals were
correlated with elevated
adrenocorticotrophic hormone (
ACTH) (64% and 104%) and
glucocorticoid production (198% and 79%) compared with YH and YS groups, respectively.
Neuroendocrine adaptive changes in SA animals were associated with
thymic hypoplasia.
Splenic T lymphocytes from animals that had self-administered
heroin showed a profoundly reduced ability to proliferate in response to
concanavalin A (50% and 48% compared with YH and YS controls, respectively; Fig. 1A), or a
monoclonal antibody (R73) to the CD3/
T-cell receptor complex (anti-TCR) plus IL-2 (55% and 59% compared with YH and YS controls, respectively; Fig. 1B). Self-administration of
heroin selectively alters
T lymphocyte function, as no effects on
natural killer cell activity or
macrophage functions were observed. These findings may have relevance to the acquisition and documented increased incidence of
infectious diseases, including
HIV, in
heroin addicts, due to a pre-existing
T-cell immunodeficient state.
