Abstract
Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. During tactile allodynia, activation of the sensory fibers which normally detect touch elicits pain. Here we provide a new behavioral investigation into the dynamic component of tactile allodynia that developed in rats after segmental removal of glycine inhibition. Using in vivo electrophysiological recordings, we show that in this condition innocuous mechanical stimuli could activate superficial dorsal horn nociceptive specific neurons. These neurons do not normally respond to touch. We anatomically show that the activation was mediated through a local circuit involving neurons expressing the gamma isoform of protein kinase C (PKCγ). Selective inhibition of PKCγ as well as selective blockade of glutamate NMDA receptors in the superficial dorsal horn prevented both activation of the circuit and allodynia. Thus, our data demonstrates that a normally inactive circuit in the dorsal horn can be recruited to convert touch into pain. It also provides evidence that glycine inhibitory dysfunction gates tactile input to nociceptive specific neurons through PKCγ-dependent activation of a local, excitatory, NMDA receptor-dependent, circuit. As a consequence of these findings, we suggest that pharmacological inhibition of PKCγ might provide a new tool for alleviating allodynia in the clinical setting.
Highlights
Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system, which generates and maintains abnormal, increased neuronal sensitivity [1]
Since the mechanical allodynia provoked by intracisternal strychnine was localized to the face, it is probable that glycine receptors were blocked at the trigeminal level only
Our initial hypothesis attempted to explain the development of tactile allodynia purely on the basis of changes in wide dynamic range (WDR) neurons [64], we found that the hyperexcitability of WDR neurons disinhibited by application of strychnine in the Sp5O was not paralleled with cardiovascular responses comparable to those evoked by nociceptive stimuli [34]
Summary
Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system, which generates and maintains abnormal, increased neuronal sensitivity [1]. A new concept has been proposed, in which pain symptoms are analyzed on the basis of underlying mechanisms [3]. Increased knowledge of pain-generating mechanisms and their translation into symptoms should allow a dissection of the mechanisms that are at play in each patient [4,5]. This, combined with a selection of drugs that act on those mechanisms should make it possible to design optimal treatments for individual patients [6]. We investigated the mechanisms of dynamic mechanical allodynia, one hallmark and disabling symptom of neuropathic pain
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
