Intraperitoneal (I.P.) injection of the endotoxin lipopolysaccharide (LPS) in rats activates an immune response that is characterised by fever (an increase in core body temperature) and hyperalgesia (as measured by increases in reponses to noxious cutaneous stimuli; Watkins & Maier, 1999). At present, it is unclear to what extent the hyperalgesia is a central effect or is secondary to the rise in core temperature and the consequent adjustments in peripheral blood flow that may result in alterations in the sensitivity of cutaneous nociceptors. To investigate this further we have compared responsiveness to noxious pinch in two models where core temperature was increased: (i) endogenously, during LPS-induced fever and (ii) exogenously, using a heated blanket.

Twenty-three alphaxalone/alphadolone (Saffan; 14-24 mg kg^-1 h^-1)-anaesthetised male rats were instrumented to record arterial blood pressure, ECG/heart rate, respiratory rate, core temperature and temperature of the stimulated paw (as an indicator of changes in peripheral blood flow). Withdrawal responses to controlled noxious pinches (1.2-1.6 N, 15 s every 5 min) of the hindpaw were monitored by recording the magnitude of biceps femoris EMG. The recorded parameters were monitored before, during and after changes in core temperature induced by: (i) LPS (0.2 mg kg^-1; I.P.) or (ii) a thermostatically controlled heating blanket; the latter was controlled to mimic precisely the changes induced by LPS. At the end of the experiment, animals were humanely killed. In control experiments, saline (as opposed to LPS) was injected I.P. and, in a second series, core temperature was maintained within physiological limits whilst paw temperature was increased (by 4°C) using a peltier heating pad placed on the plantar surface of the stimulated hindpaw.

After a delay of between 60 and 120 min there was an increase in core temperature in LPS treated rats (peak 38.37 ± 0.24 ^oC; duration 180 ± 28 min; n = 6) and the magnitude of EMG increased significantly by 52.12 ± 24.76 % (P < 0.05, Student’s paired t test) over the same time course. In contrast, in exogenously heated animals (peak 39.06 ± 0.17 °C; duration 180 ± 10 min) there was a significant decrease (-44.56 ± 15.9 %) in EMG magnitude (P < 0.05, Student’s paired t test). During increased core temperatures, paw temperatures decreased (-2.04 ± 0.29 °C) in LPS-treated animals and, in contrast, increased (4.28 ± 1.8 °C) in heated animals. There were no significant changes in core temperature or EMG responses in control animals in which the paw temperature was increased (n = 5) or in those injected with saline I.P. (n = 6).

These data indicate that the hyperalgesia associated with immune responses is not secondary to changes in core temperature and consequent adjustments in peripheral blood flow. They support the view that changes in sensory experience associated with fever may involve immune to brain communication and modulation of the central processing of nociceptive information.C.L.B. is a MRC scholar. This work was supported by The Wellcome Trust and the British Heart Foundation.

Watkins, L.R. & Maier, S.F. (1999). Proc. Natl Acad. Sci. USA 96, 7710-7713.