Interleukin-1 signaling in the basolateral amygdala is necessary for heroin-conditioned immunosuppression

Abstract

Heroin administration suppresses the production of inducible nitric oxide (NO), as indicated by changes in splenic inducible nitric oxide synthase (iNOS) and plasma nitrate/nitrite. Since NO is a measure of host defense against infection and disease, this provides evidence that heroin can increase susceptibility to pathogens by directly interacting with the immune system. Previous research in our laboratory has demonstrated that these immunosuppressive effects of heroin can also be conditioned to environmental stimuli by repeatedly pairing heroin administration with a unique environmental context. Re-exposure to a previously drug-paired context elicits immunosuppressive effects similar to heroin administration alone. In addition, our laboratory has reported that the basolateral amygdala (BLA) and medial nucleus accumbens shell (mNAcS) are critical neural substrates that mediate this conditioned effect. However, our understanding of the contributing mechanisms within these brain regions is limited. It is known that the cytokine interleukin-1 (IL-1) plays an important role in learning and memory. In fact, our laboratory has demonstrated that inhibition of IL-1β expression in the dorsal hippocampus (DH) prior to re-exposure to a heroin-paired context prevents the suppression of measures of NO production. Therefore, the present studies sought to further investigate the role of IL-1 in heroin-conditioned immunosuppression. Blockade of IL-1 signaling in the BLA, but not in the caudate putamen or mNAcS, using IL-1 receptor antagonist (IL-1Ra) attenuated heroin-conditioned immunosuppression of NO production as measured by plasma nitrate/nitrite and iNOS mRNA expression in spleen tissue. Taken together, these findings suggest that IL-1 signaling in the BLA is necessary for the expression of heroin-conditioned immunosuppression of NO production and may be a target for interventions that normalize immune function in heroin users and patient populations exposed to opiate regimens.

Keywords: Basolateral amygdala; Heroin; IL-1; IL-1 receptor antagonist; Immune conditioning, opioid; Learning; Nitric oxide.

Fig. 1

Illustration of cannula placement. Symbols represent the ventral most point of the injection cannula tracts in the (A) BLA, (B) pCPu, and (C) mNAcS. Numbers represent distance from bregma based on the rat brain atlas of Paxinos and Watson (2009).

Fig. 2

Effects of BLA IL-1 antagonism on LPS-induced expression of splenic iNOS mRNA (A) and protein (B) and plasma nitrate/nitrite (C). For mRNA data, mean displayed is % of saline-treated home cage control. Sample sizes range from n = 4–6 per group. Symbols (*) represent statistically significant difference relative to respective home cage control group (p < 0.05).

Fig. 3

Effects of pCPu IL-1 antagonism on LPS-induced expression of splenic iNOS mRNA (A) and protein (B) and plasma nitrate/nitrite (C). For mRNA data, mean displayed is % of saline-treated home cage control. Sample sizes range from n = 6–7 per group. Symbols (*) represent statistically significant difference relative to respective home cage control group (p < 0.05).

Fig. 4

Effects of mNAcS IL-1 antagonism on LPS-induced expression of splenic iNOS mRNA (A) and protein (B) and plasma nitrate/nitrite (C). For mRNA data, mean displayed is % of saline-treated home cage control. Sample sizes range from n = 6–7 per group. Symbols (*) represent statistically significant difference relative to respective home cage control group (p < 0.05).