Spinal bicuculline produces hypersensitivity of dorsal horn neurons: effects of excitatory amino acid antagonists

Abstract

In this study, we sought to characterize the effects of focal GABA(A) receptor antagonism on spontaneous and evoked activity in dorsal horn neurons of the alpha-chloralose anesthetized cat. Bicuculline (0.5, 1.0 mM) applied near the neurons through a transparenchymal dialysis fiber resulted in increased evoked activity in nociceptive dorsal horn neurons. Hair deflection was the stimulus most affected, followed by both low and high threshold tonic mechanical stimulation of the receptive field. In addition, neurons displayed increased background discharge and a subpopulation developed an increased afterdischarge to noxious mechanical stimulation. This is in contrast to our previous work with glycine receptor antagonism where only the evoked response to hair follicle activation was significantly enhanced. Subsequent co-administration of an NMDA receptor antagonist (AP-7, 2.0 mM) was without any apparent effect on either basal or bicuculline-enhanced responses. Co-administration of a non-NMDA excitatory amino acid receptor antagonist (CNQX, 1.0 mM) with the bicuculline non-selectively blocked both low and high threshold mechanical input. The inability of AP-7 to reverse the bicuculline-associated hyperreactivity also contrasts with the AP-7 reversal of the strychnine-associated hyperreactivity. These results point out that, while GABA and glycine are frequently co-localized in cells of the spinal dorsal horn and both appear to mediate tonic inhibitory control systems, they are not at all equivalent and are subject to different modulatory pharmacologies. Removal of each influence may model a different component of neuropathic pain.

Peripheral nerve injury alters spinal nicotinic acetylcholine receptor pharmacology

“…The difference between the studies of Abdin et al (2006) and the current study is likely due to the intensity of the mechanical stimuli used. Spinal GABA A and glycine receptors inhibit tactile allodynia (Sivilotti and Woolf, 1994;Sorkin et al, 1998), but only GABA A receptors inhibit hypersensitivity to high intensity stimuli (Sorkin et al, 1998).…”

Activation of Cannabinoid CB2Receptors Suppresses C-Fiber Responses and Windup in Spinal Wide Dynamic Range Neurons in the Absence and Presence of Inflammation

“…However, noxious input can quickly enhance the sensitivity of spinal neurons for further C-fiber inputs. Spinal neuronal excitability may increase through several mechanisms including: 1) a cumulative depolarization that lowers the threshold for action potential initiation (induced by increased spontaneous or ongoing activity of primary afferents) (Sivliotti et al 1993), 2) presynaptic facilitation (e.g., increased excitatory amino acid or tachkinin release evoked by prior primary afferent activation) (Gerber and Randic 1989;Urban and Randic 1984;Yoshimura and Jessell 1990), and 3) increased efficacy of postsynaptic receptors induced by prior activation of spinal neurons (e.g., because of facilitation of signal transduction/second messenger coupling and/or receptor upregulation) (Schmidt 1971;Sorkin and Puig 1996;Sorkin et al 1998). In the present study, increased WDR neuronal excitability likely resulted from the summation of depolarizing postsynaptic potentials in WDR neurons and/or presynaptic facilitation because these changes can occur within minutes, whereas an increase in postsynaptic receptor number or efficacy takes much longer.…”

Properties of Layer 6 Pyramidal Neuron Apical Dendrites

“…A recent study showed that the first-order thalamic relay, which provides numerous terminations in L4 (Sorkin et al, 1998;Gil et al, 1999;Sherman and Guillery, 2002;Bruno and Sakmann, 2006), in fact contacts L6 pyramidal neurons predominantly on Figure 11. Activation of distal inhibitory inputs induces a long-lasting blockade of dendritic Ca 2ϩ electrogenesis.…”