Neuroimmune mechanisms of opioid-mediated conditioned immunomodulation

Abstract

Morphine administration elicits pronounced effects on the immune system, including decreases in natural killer (NK) cell activity and lymphocyte mitogenic responsiveness. These immune alterations can become conditioned to environmental stimuli that predict morphine as a result of Pavlovian conditioning processes. Prior work in our laboratory has shown that acute morphine exposure produces dopamine-dependent reductions of NK cell activity that are mediated peripherally by neuropeptide Y Y1 receptors. The present study examined the involvement of dopamine D1 and neuropeptide Y Y1 receptors in the conditioned immunomodulatory effects of morphine. Rats received two conditioning sessions during which an injection of morphine was paired with a distinctive environment which served as the conditioned stimulus (CS). The results show that systemic administration of the D1 antagonist SCH-23390 prior to CS re-exposure prevented the conditioned suppression of splenic NK activity but did not alter conditioned decreases in mitogen-induced lymphocyte proliferation. Furthermore, bilateral microinjections of SCH-23390 directly into the nucleus accumbens shell fully blocked conditioned changes in NK activity. In a subsequent manipulation, subcutaneous injection of the Y1 receptor antagonist BIBP3226 prior to CS re-exposure was also shown to prevent conditioned effects on NK activity. Collectively, these findings provide evidence that the nucleus accumbens shell plays an important role in conditioned immunomodulation and further suggest that the conditioned and unconditioned immunomodulatory effects of opioids involve similar receptor mechanisms.

Fig. 1

Effect of systemic dopamine D₁ receptor antagonism on conditioned suppression of splenic NK cell activity. Subcutaneous administration of SCH-23390 at a dose of 0.5 mg/kg reversed the inhibition of splenic NK activity induced by CS re-exposure. Data are expressed as lytic units (mean ± S.E.). Solid bars indicate rats that remained in their home cages on the test day and open bars represent groups re-exposed to the CS on the test day. *p < 0.01; **p < 0.001 compared with the home cage group that received the same dose of SCH-23390.

Fig. 2

Effect of systemic D₁ receptor antagonism on conditioned suppression of lymphocyte proliferation. Subcutaneous SCH-23390 administration did not attenuate the inhibitory effect of CS re-exposure on splenocyte mitogenic responses to Con-A (5.0 μg/ml) or LPS (5.0 μg/ml). Data are expressed as disintegrations per minute (mean ± S.E.). Solid bars indicate rats that remained in their home cages on the test day and open bars represent groups re-exposed to the CS on the test day. *p < 0.01; **p < 0.001 compared with the home cage group that received the same dose of SCH-23390.

Fig. 3

Effect of D₁ receptor antagonism in the nucleus accumbens shell (A) or core (B) on conditioned suppression of NK cell activity. A, Bilateral injections of SCH-23390 into the nucleus accumbens shell blocked the inhibitory effect of CS re-exposure on NK activity. B, Administration of SCH-23390 into the nucleus accumbens core did not prevent the effect of CS re-exposure. Solid bars indicate rats that remained in their home cages on the test day and open bars represent groups re-exposed to the CS on the test day. Data are expressed as lytic units (mean ± S.E.). *p < 0.01; **p < 0.001 compared with the home cage group that received the same dose of SCH-23390.

Fig. 4

Effect of NPY Y₁ receptor antagonism on conditioned reductions of NK cell activity. Subcutaneous administration of BIBP3226 at a dose of 1.0 mg/kg blocked the inhibition of splenic NK activity induced by CS re-exposure. Solid bars indicate rats that remained in their home cages on the test day and open bars represent groups re-exposed to the CS on the test day. *p < 0.05; **p < 0.001 compared with the home cage group that received the same dose of BIBP3226.