The endogenous cytokine profile and nerve fibre density in mouse ear Leishmania major-induced lesions related to nociceptive thresholds

Abstract

Several reports have shown that cutaneous leishmaniasis lesions are painless, suggesting that Leishmania infection interferes with pain perception. Comparisons of inflammation-induced hyperalgesia between BALB/c and C57BL/6 mice have been little explored in the literature, and comparative data regarding nociception in leishmaniasis are non-existent. In susceptible BALB/c mice and resistant C57BL/6 mice that were intradermally inoculated with a low dose of Leishmania major in the ear, we investigated the variation in nociception over a 12-wk period post-infection and this variation's association with the structure of nerve fibres and the presence of endogenous cytokines that are classically considered hyper- or hypo-nociceptive. Infected BALB/c mice presented susceptibility and severe lesions. Infected C57BL/6 mice exhibited resistance and healing lesions. The immune response involved pro- and anti-inflammatory cytokine secretion, respectively. The infection-induced hypoalgesia in BALB/c mice after wks 9 was accompanied by decreased levels of IL-6 and IL-10 in ear tissue with intact nerves. C57BL/6 mice showed short-lived hyperalgesia in wks 2, which was related to increased local levels of IL-6, KC/CXCL-1, TNF-α and IL-10 and a decrease in nerve density. The increase in pro-inflammatory cytokine IL-6, KC/CXCL-1 and TNF-α levels during hyperalgesia suggested a role for these mediators in afferent nerve sensitisation, which was secondary to the inflammatory damage of nerve fibres stained by PGP 9.5. In contrast, the mechanisms of hypoalgesia may include the downregulation of cytokines, the preservation of the structure of nerve endings, and as yet uninvestigated unidentified differences in neurotransmitter release or a direct role of the parasites in the context of the progressive and permissive inflammatory response of BALB/c mice.

Profiling of how nociceptor neurons detect danger – new and old foes

“…Depending on the strain, leishmanial infections can lead to either hypoalgesia or hyperalgesia . Thus, the inflammatory mediators found in the nerve , spinal cord and brain of infected mice can trigger peripheral and central sensitization.…”

Glucantime reduces mechanical hyperalgesia in cutaneous leishmaniasis and complete Freund's adjuvant models of chronic inflammatory pain

“…As demonstrated here and in other infections, studies with parasites of the genus Leishmania, as well as, stimulation with CFA promote the development of chronic inflammatory lesions characterized by cytokines production with consequent tissue damage and pain . Specifically, CFA is one of the most commonly used agents to mimic chronic inflammation in animal models promoting tissue damage and pain, which after CFA injection into the footpad, the cutaneous inflammation appears within 2 h and peaks within 6 to 8 h, while hyperalgesia and edema are present for approximately 1 to 2 week and consequently proinflammatory cytokine production such IL‐1β, TNF‐α and IL‐6 …”

“…Previous reports have evidenced that long‐term infection with L. amazonensis (MHOM/BR/1989/166MJO) shows an induction of a strong inflammatory response in the site infection, induces hyperalgesia, parasite migration and injury in secondary organs such as spleen and liver in BALB/c mice . Despite evidence shows the absence of pain in cutaneous lesions in patients, consistent nociceptive behaviour was observed in mice and rats infected with L. major and L. amazonensis …”

“…Patients with cutaneous lesions report no pain according to most authors, while some report this sensation . Increasing experimental evidence in rodents with Leishmania major observed pain behaviour dependent on hyperalgesic cytokines production …”

Study of the µ opioid receptor in cutaneous ulcers of leishmaniasis and sporotrichosis according to the complaints of local pain

“…Both diseases share similar histopathological aspects [2]. Some experimental studies on nociception in leishmaniasis have been performed in order to better understand the profi le of cytokines related to pain, without a satisfactory conclusion [15,16]. The purpose of this study was to determine the profi le of MOR staining in the well established cutaneous ulcerated lesions of leishmaniasis and sporotrichosis in patients from Rio de Janeiro, Brazil, and to associate the MOR staining profi le with the presence or absence of pain in the cutaneous lesions of both diseases.…”