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.

Early-Life Experience Decreases Drug-Induced Reinstatement of Morphine CPP in Adulthood via Microglial-Specific Epigenetic Programming of Anti-Inflammatory IL-10 Expression

“…We determined that IL-10 protein was significantly increased in serum following morphine treatment in both groups, though significantly less so in handled rats, consistent with the literature indicating that morphine is immunosuppressive within the periphery (Sacerdote, 2008; Budd, 2006). We suspect that the differential glial response within the NAcc may be driving the differential peripheral immunosuppressive response between these groups, and consistent with this idea others have reported that the NAcc is necessary for the peripheral immunosuppression induced by morphine (Saurer et al, 2008; Saurer et al, 2009). Nonetheless, the contribution of peripheral immune cells to morphine reward and relapse and their modulation by early-life experience cannot be completely ruled out.…”

“…Taken together, these data indicate that morphine is immunosuppressive within the periphery, but that neonatal handling does not program baseline IL-10 expression within the peripheral immune system as it does within the brain. Rather, we hypothesize that the difference in peripheral immunosuppression following morphine administration between handled and non-handled control rats is driven by the differential glial response within the NAcc as it has been reported that the NAcc is necessary for the peripheral immunosuppression induced by morphine (Saurer et al, 2008; Saurer et al, 2009). …”

Naloxone can improve the anti-tumor immunity by reducing the CD4+CD25+Foxp3+ regulatory T cells in BALB/c mice

“…Opioid peptides are well known effectors of in vivo and in vitro immune responses. Furthermore, it has been shown that the opioids have broad immunomodulatory activity, both on cellular and humoral immune responses and are able to modulate inflammatory cytokine production [9][10][11]. This immunomodulatory activity is mediated by either the µ, δ or κ opioid receptors that are expressed on immune cells.…”

Region-specific contribution of the ventral tegmental area to heroin-induced conditioned immunomodulation

“…In support of this, inactivation of the BLA and blockade of dopamine D 1 -like receptors within the BLA prevent the suppressive effect of the heroin-associated context on iNOS induction and on TNF-α and IL-1β expression in spleen and liver tissue (Szczytkowski and Lysle, 2008, 2010). Dopamine D 1 -like receptor antagonism in the NAc shell blocks the expression of morphine-induced conditioned immune alterations (Saurer et al, 2008b). In a recent functional disconnection study from our laboratory (Szczytkowski et al, 2011), we provided evidence that the NAc plays a critical role in heron-conditioned immunomodulation as an element of a larger VTA-BLA-NAc circuit.…”

“…Findings from our laboratory demonstrated that dopamine receptor activity was necessary for the expression of opioid-conditioned immune alterations, as administration of a D 1 -like receptor antagonist prior to re-exposure to a morphine-conditioned stimulus prevented the suppression of natural killer cell activity (Saurer et al, 2008a). Similar immunomodulatory effects have also been demonstrated with heroin (Fecho and Lysle, 2000; Lysle and Ijames, 2002; Saurer et al, 2008a). …”