Abstract
Endothelin-1 (ET-1) is an endogenously expressed potent peptide vasoconstrictor. There is growing evidence that ET-1 plays a role in the pain signaling system and triggers overt nociception in humans. The underlying neuronal pathways are still a matter of great debate. In the present study, we applied an intradermal ET-1 sensitization model to induce mechanical hyperalgesia in healthy subjects. Functional magnetic resonance imaging (fMRI) was used to tease out the cortical regions associated with the processing of ET-1-induced punctate hyperalgesia, as compared to a nonnoxious mechanical stimulation of the contralateral arm. Von Frey hair testing revealed the presence of increased responsiveness to punctate stimulation in all subjects. Activational patterns between nonpainful control stimulation and hyperalgesic stimulation were compared. Two major observations were made: (1) all cortical areas that showed activation during the control stimulation were also present during hyperalgesic stimulation, but in addition, some areas showed bilateral activation only during hyperalgesic stimulation, and (2) some brain areas showed significantly higher signal changes during hyperalgesic stimulation. Our findings suggest that injection of ET-1 leads to a state of punctate hyperalgesia, which in turn causes the activation of multiple brain regions. This indicates that ET-1 activates an extended neuronal pathway.
Highlights
Pain is a complex and often difficult to treat condition, with different etiologies, locations, and symptoms
Our findings suggest that injection of ET-1 leads to a state of punctate hyperalgesia, which in turn causes the activation of multiple brain regions
We have demonstrated that our ET-1-induced hyperalgesic model induces activation of a complex neuronal network
Summary
Pain is a complex and often difficult to treat condition, with different etiologies, locations, and symptoms. Endothelin-1 (ET-1), a 21 amino acid residue peptide, is one such possible pain mediator. Recognized as a potent vasoconstrictor [1], ET-1 has been shown to possess nociceptive properties in animals and pain-inducing properties in humans. It has been postulated that ET-1 is involved in driving acute and chronic pain conditions from different etiologies [2]. Receptors for ET-1 are found in neurons throughout the CNS [5]. Such presence of ET-1 and its receptors in nervous tissues suggests its possible role as a neurotransmitter and/or neuromodulator. Endogenous endothelins contribute significantly to the pain and/or hyperalgesia of inflammatory, immune, neuropathic, and neoplastic origins [17,18,19,20]
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