Skip to main content
. Author manuscript; available in PMC: 2006 May 30.
Published in final edited form as: Curr Top Med Chem. 2005;5(6):547–555. doi: 10.2174/1568026054367629

Fig. (2).

Fig. (2)

Three mechanisms of altered Cl− homeostasis that enhance nociception by facilitating low threshold input to nociceptive neurons. The general diagram on the left illustrates how gating of the nociceptive input at spinal level can affect pain perception at the cortical level. The enlarged diagram on the right serves to illustrate distinct mechanisms by which low threshold (innocuous) input from large caliber afferents may be conveyed to nociceptive relay neurons, offering a substrate for touch evoked allodynia. For the sake of simplicity, the green GABA- and or glycinergic interneuron is represented as a single cell, but different interneuronal pathways may be involved. The numbers next to the interneuron represent one of the three possible mechanisms: 1) Exaggerated Primary Afferent Depolarization (PAD): Activity in low threshold non-nociceptive afferents activates GABAergic interneurons (shown in green) that release GABA onto the nociceptive afferent terminals. The activation of GABA-A receptors opens Cl− channels and Cl− ions flow out, partially depolarizing the membrane of the primary afferents (PAD). Enhanced activity of NKCC1 in the nociceptive afferent terminal would lead to an increased intracellular Cl− concentration, and therefore to a larger GABA-induced depolarization. This enhanced depolarization can reach firing threshold, producing action potentials in the nociceptive afferent terminal evoked by impulses in the low threshold afferent. 2) Disinhibition of polysynaptic pathways to nociceptive neurons: Low threshold afferents can excite feed-forward excitatory interneurons contacting nociceptive projection neurons. Excitability of these neurons can be maintained low by local GABA/glycinergic interneurons. Decreased KCC2 expression/activity in both the feed-forward and/or the nociceptive projecting neuron can unmask normally subliminal input to the latter from low threshold afferents. 3) Direct relay of low threshold input to nociceptive neurons via GABA/glycinergic interneuron: Following decreased KCC2 expression/activity in nociceptive projecting neurons input from low threshold afferents that would normally cause inhibition of the relay cell can now cause a net excitation of this neuron.