Abstract
Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis. The subcutaneous administration of TTX dose-dependently inhibited the number of pain-related behaviors in all evaluated pain models and reversed the referred mechanical hyperalgesia (examined by stimulation of the abdomen with von Frey filaments) induced by capsaicin and cyclophosphamide, but not that induced by mustard oil. Morphine inhibited both pain responses and the referred mechanical hyperalgesia in all tests. Conditional nociceptor‑specific Nav1.7 knockout mice treated with TTX showed the same responses as littermate controls after the administration of the algogens. No motor incoordination after the administration of TTX was observed. These results suggest that blockade of TTX-sensitive sodium channels, but not Nav1.7 subtype alone, by systemic administration of TTX might be a potential therapeutic strategy for the treatment of visceral pain.
Highlights
Visceral pain is the pain originating from the internal organs caused by a variety of diseases; it the most common form of pathological pain and represents a major reason for patients to seek medical consultation [1,2,3]
We have evaluated the antinociceptive effects of TTX in three different visceral pain models in mice: the intracolonic administration of both capsaicin [24,25] and mustard oil [26,27] and a model of cyclophosphamide-induced cystitis [27,28]
As a control analgesic drug, we used morphine (8 mg/kg, s.c.), which fully abolished the pain-related behaviors produced by capsaicin and mustard oil, even below those observed in the vehicle + saline group (Figure 1A,B)
Summary
Visceral pain is the pain originating from the internal organs caused by a variety of diseases; it the most common form of pathological pain and represents a major reason for patients to seek medical consultation [1,2,3]. Despite its prevalence, the treatment of visceral pain is complex and the current available pharmacological treatments have limited efficacy, making it necessary to develop effective drugs against this painful condition [4]. Visceral pain has unique characteristics that differentiate it from somatic pain, which the response of visceral and somatic pain to drug treatment different; most of our knowledge about pain mechanisms derives from experimental studies of somatic rather than visceral pain [5,6,7]. Mar. Drugs 2017, 15, 188; doi:10.3390/md15060188 www.mdpi.com/journal/marinedrugs. Mar. Drugs 2017, 15, 188 are still poorly understood; the development of animal models of visceral pain is allowing for the specific peripheral and central mechanisms involved to be investigated [8]
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