Postdoctoral scholar Oregon Health & Science University Portland, Oregon
Interleukin-1β (IL-1β) induces neuroimmune responses that help to fight infections. IL-1β-induced fever is not abolished by cyclooxygenase (COX) inhibitors used to treat inflammation and the neural pathways responsible for COX-independent fever are still unknown. Considering that neurons that reside in the rostral raphe pallidus area (rRPa) and in the dorsomedial hypothalamus (DMH) play a key role in the control of thermoeffectors, we hypothesized that neurons in these areas contribute to COX-independent fever elicited by intravenous (iv) IL-1β. Female and male Sprague Dawley rats were anesthetized with urethane and α-chloralose (ur/ch) or isoflurane (iso) and treated with saline or indomethacin, prior to receiving iv IL-1β. Systemic IL-1β increased brown adipose tissue (BAT) sympathetic nerve activity (SNA) (+2852 ± 2020% baseline (BL), p = 0.003), BAT temperature (TBAT; +2.6 ± 1.3°C, p lt; 0.001), expired CO2 (+1.0 ± 0.4%, p lt; 0.001), core body temperature (TCORE; +0.6 ± 0.2°C, p lt; 0.001), heart rate (HR; +102 ± 42 bpm, p lt; 0.001), mean arterial pressure (MAP; +11 ± 7 mmHg, p = 0.002), and paw temperature (TPAW; -6.9 ± 1.2°C, p lt; 0.001), which is an index of cutaneous vasoconstriction (CVC). Indomethacin did not prevent IL-1β-evoked increases in BAT SNA (+2545 ± 756% BL, p lt; 0.001), TBAT (+2.9 ± 1.3°C, p lt; 0.001), expired CO2 (+1.2 ± 0.6%, p = 0.003), TCORE (+0.9 ± 0.5°C, p = 0.005), HR (+117 ± 47 bpm, p lt; 0.001), MAP (+27 ± 20 mmHg, p = 0.01), or TPAW (-5.9 ± 3.4°C, p = 0.02). Nanoinjection of muscimol in the rRPa prevented IL-1β-evoked increases in BAT SNA (p lt; 0.01), TBAT (p lt; 0.01), expired CO2 (p lt; 0.01) and TCORE (p lt; 0.01), but not in HR (p = 0.08), in comparison to the group that received IL-1β only. Nanoinjection of muscimol in the rRPa in indomethacin-pretreated rats prevented IL-1β-evoked increases in BAT SNA (p lt; 0.01), TBAT (p lt; 0.01), expired CO2 (p lt; 0.01), TCORE (p lt; 0.01), and TPAW (p = 0.03), but not in HR (p = 0.12), in comparison to an indomethacin-pretreated group that received IL-1β. Nanoinjections of glutamate receptor antagonists in the DMH markedly reduced IL-1β-evoked increases in BAT SNA (-838 ± 542% BL, p = 0.03), TBAT (-1.1 ± 0.4°C, p = 0.003), expired CO2 (-0.4 ± 0.1%, p = 0.009) and HR (-38 ± 20 bpm, p = 0.01), and reduced MAP (-4 ± -2 mmHg, p = 0.02). Plasma PGE2 levels following iv IL-1β were significantly higher (by ~3 fold) in rats that were not anesthetized when receiving IL-1b (263.1 ± 136.4 pg/ml) compared to all other groups of rats that were maintained under anesthesia for 2 h (ur/ch anesthetized, saline pretreated: 96.7 ± 30.8 pg/ml, p = 0.007, or indomethacin pretreated: 119.7 ± 51.9 pg/ml, p = 0.02; iso anesthetized, saline pretreated: 82.5 ± 21.2 pg/ml, p = 0.003, or indomethacin-pretreated: 108.4 ± 39.1 pg/ml, p = 0.01). Therefore, we suggest that the anesthetics used inhibited the systemic production of PGE2. Together, our data suggest that a glutamatergic input to the DMH is necessary for providing the excitatory drive for increasing BAT thermogenesis and tachycardia in response to circulating IL-1β, likely via rRPa neurons. Additionally, IL-1β-evoked CVC requires activation of neurons in the rRPa. These data define critical components of the neural circuit for systemic IL-1β-induced fever and provide a foundation for elucidating additional brain mechanisms responsible for COX-independent fever.
