Abstract
Infection with a high dose of the intracellular parasitic protozoan Leishmania major induces a sustained hyperalgesia in susceptible BALB/c mice accompanied by up-regulation of the pro-inflammatory cytokines IL-1β and IL-6. Interleukin-13 (IL-13) has been shown to reduce this hyperalgesia (despite increased levels of IL-6) and the levels of IL-1β during and after the treatment period. These findings favor the cytokine cascade leading to the production of sympathetic amines (involving TNF-α and KC) over prostaglandins (involving IL-lβ and IL-6) as the final mediators of hyperalgesia. The aim of this study was to investigate the effect of daily treatment with the β-blockers atenolol on L. major-induced inflammation in mice with respect to hyperalgesia as well as the levels of TNF-α and KC (the analog of IL-8 in mice). Our data demonstrates that atenolol is able to reduce the L. major induced sustained peripheral hyperalgesia, which does not seem to involve a direct role for neither IL-lβ nor KC. Moreover, our results show that TNF-α may play a pivotal and direct role in sensitizing the peripheral nerve endings (nociceptors) since its level was reduced during the period of atenolol treatment, which correlates well with the reduction of the observed peripheral, but not central, hyperalgesia. These findings contribute to a better understanding of the cytokine cascade leading to hyperalgesia and may lead to the development of new and more efficient medications for many types of pain.
Highlights
The course and outcome of cutaneous leishmaniasis caused by the parasite Leishmania major depends on the type of immune response mounted by the host, whereby the humoral and the cell-mediated responses are, respectively, associated with the susceptibility and resistance to the prevailing infection (Cunningham, 2002), because these parasites have the capacity to escape the humoral response by residing in the phagolysosomes of macrophages
In the cutaneous leishmaniasis model, the subcutaneous injection of high dose of L. major in the paws of BALB/c mice causes a sustained hyperalgesia accompanied by an increase in the levels of pro-inflammatory cytokines IL-lβ and nerve growth factor (NGF) (Kanaan et al, 2000) while infection with a low dose of the parasite causes a short lived hyperalgesia accompanied by the upregulation of interleukin 1β (IL-1β) and IL-6 (Karam et al, 2006)
Atenolol did not affect the levels of IL-lβ giving further evidence that this cytokine does not play a direct role in peripheral or central hyperalgesia, which is in accordance with previous studies performed by our group (Karam et al, 2011)
Summary
The course and outcome of cutaneous leishmaniasis caused by the parasite Leishmania major depends on the type of immune response mounted by the host, whereby the humoral and the cell-mediated responses are, respectively, associated with the susceptibility and resistance to the prevailing infection (Cunningham, 2002), because these parasites have the capacity to escape the humoral response by residing in the phagolysosomes of macrophages. Regardless of the course and outcome of the infection, the induced inflammatory response involves hyperalgesia, which is the enhancement of pain sensitivity to noxious stimuli and spontaneous pain (Driessen, 2007; Cervero, 2009) due to sensitization of nociceptors (hypernociception). Peripheral sensitization is an increased responsiveness to stimuli by the peripheral ends of nociceptors These neurons transfer signals from peripheral targets (skin, joints, muscle, and viscera) to the central nervous system (Spinal cord and brainstem) (Woolf and Ma, 2007). Even though pain hypersensitivity is mainly based on peripheral sensitization, high levels of activity lead to the activation of dorsal horn nociceptors resulting in the modification of sub threshold innocuous stimuli so that they activate second order neurons in the dorsal horn giving rise to a central sensation of pain which is so called allodynia (Kidd and Urban, 2001)
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