Wasting syndrome is a common complication of HIV
Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever (Weinroth et al., 1995). Fever is a highly complex process initiated by the action on the p450 inhibitors thermosensitive cells of a number of endogenous pyrogens, which are produced by the host in response to infectious as well as non-infectious inflammatory insults (Blatteis and Sehic, 1997). It is believed to be caused by the synthesis and release from monocytes and macrophages of a number of well characterized endogenous pyrogenic factors (Blatteis, 2006). The participation of the opioid system in the pathogenesis of fever has been previously reported (Benamar et al., 2000, Benamar et al., 2002a). Specifically, we have shown that mu-opioid receptors in the POAH are implicated in the inflammatory response to bacterial LPS and endogenous pyrogens (Benamar et al., 2000, Benamar et al., 2002a). Mu opioid receptors within the POAH have been found to be involved in the fever induced by interleukin-6 (IL-6) (Benamar et al., 2002a), as pretreatment with the selective mu-opioid antagonist (CTAP) significantly blocked the IL-6-induced fever. Moreover, LPS failed to produce fever in mice lacking the mu opioid receptor (Benamar et al., 2005).
HIV-1 enters cells through interaction of glycoprotein (gp120) with host CD4 and specific chemokine receptors (Feng et al., 1996). gp120 has been detected in the brains of HIV-1-infected individuals (Jones et al., 2000). It is released by infected cells (Schneider et al., 1986) and may be toxic to certain uninfected cells (Lipton, 1991). It is implicated in the pathogenesis of neurological disorders associated with HIV. In rodents, the presence of gp120 in the brain has been associated with several neurobehavioral alterations. In particular, it has been shown that intracerebroventricular injection of gp120 in rats produced a marked sickness behavior syndrome, consisting of reduced exploratory behavior, suppressed consumption of food and saccharin solution, and reduced body weight and fever (Barak et al., 2002).
Recently, we have shown that gp120 given directly into the preoptic anterior hypothalamus (POAH), the main brain area for the control of body temperature (Tb) was able to induce a significant increase in Tb in a dose-related manner (Benamar et al., 2010). The aim of the present study was to investigate whether pharmacological manipulation of the opioid system at level of this brain area interferes with febrile response induced by gp120.
Results To determine the role of the opioid system in the gp120-induced fever, first we used a general opioid antagonist, naloxone. While a dose of 1mg/kg had no effect on gp120-induced fever, the pretreatment with naloxone at doses of 5 and 10mg/kg significantly attenuated the fever induced by gp120 (Fig. 1A). The administration of naloxone (10mg/kg s.c.) had no significant effect by itself on Tb (Fig. 1A). To identify which specific opioid receptor is responsible for the effect of naloxone on gp120-induced fever, we used selective opioid receptor antagonists. Previously, it has been shown that kappa opioid receptor activation produces hypothermia and the activation of mu or delta-2 opioid receptors induces hyperthermia (Geller et al., 1983, Benamar et al., 2002b). Therefore, we examined specific mu and delta receptor antagonists. We have also previously found that the mu-selective antagonist CTAP was effective at reducing the febrile response of LPS and IL-6 (Benamar et al., 2000, Benamar et al., 2002a). As seen in Fig. 1B, CTAP attenuated gp120-induced fever (F2,28=5.45, P<0.001). The dose of CTAP (1μg) used had no effect by itself on Tb (Fig. 1B). To determine whether delta opioid receptors play a role in the pathogenesis of the fever induced by gp120, we pretreated the rats with NTB, a potent and selective antagonist for the delta-2 opioid receptor. Previously, we have examined the effect of the intra-POAH injection of NTB, by itself, on Tb (Benamar et al., 2004). NTB at a dose that has no effect on Tb (1μg) was used to determine whether delta-2 receptors are implicated in the febrile response induced by gp120. NTB was injected directly into the POAH 30min prior to gp120 (133ng). In contrast to CTAP, NTB did not cause any effect on gp120-induced fever (Fig. 2.).