Superficial NK1 expressing spinal dorsal horn neurones modulate inhibitory neurotransmission mediated by spinal GABA(A) receptors.
Lamina 1 projection neurones which express the NK1 receptor (NK1R+) drive a descending serotonergic pathway from the brainstem that enhances spinal dorsal horn neuronal activity via the facilitatory spinal 5-HT3 receptor. Selective destruction of these cells via lumbar injection of substance P-saporin (SP-SAP) attenuates pain behaviours, including mechanical and thermal hypersensitivity, which are mirrored by deficits in the evoked responses of lamina V-VI wide dynamic range (WDR) neurones to noxious stimuli. To assess whether removing the origin of this facilitatory spino-bulbo-spinal loop results in alterations in GABAergic spinal inhibitory systems, the effects of spinal bicuculline, a selective GABA(A) receptor antagonist, on the evoked neuronal responses to electrical (Abeta-, Adelta-, C-fibre, post-discharge and Input) and mechanical (brush, prod and von Frey (vF) 8 and 26 g) stimuli were measured in SAP and SP-SAP groups. In the SAP control group, bicuculline produced a significant dose related facilitation of the electrically evoked Adelta-, C-fibre, post-discharge and input neuronal responses. The evoked mechanical (prod, vF8 g and 26 g) responses were also significantly increased. Brush evoked neuronal responses in these animals were enhanced but did not reach significance. This facilitatory effect of bicuculline, however, was lost in the SP-SAP treated group. The generation of intrinsic GABAergic transmission in the spinal cord appears dependent on NK1 bearing neurons, yet despite the loss of GABAergic inhibitory controls after SP-SAP treatment, the net effect is a decrease in spinal cord excitability. Thus activation of these cells predominantly drives facilitation.
Rahman
Wahida
W
Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. w.rahman@ucl.ac.uk
Sikandar
Shafaq
S
Sikander
Shafaq
S
Suzuki
Rie
R
Hunt
Stephen P
SP
Dickenson
Anthony H
AH
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013373:Substance P / Q000031:analogs & derivatives / Q000633:toxicity; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D018756:GABA Antagonists; D011963:Receptors, GABA-A; D018040:Receptors, Neurokinin-1; D054789:Ribosome Inactivating Proteins, Type 1; C468274:substance P-saporin; D013373:Substance P; D000076985:Saporins; D001640:Bicuculline