Strychnine-sensitive modulation is selective for non-noxious somatosensory input in the spinal cord of the rat

Abstract

Touch-evoked allodynia, an important symptom of clinical neural injury pain, can be modelled acutely and reversibly in the urethane-anesthetized rat using intrathecal (i.t.) strychnine (STR). Allodynia, after i.t. STR (40 micrograms), is manifest as a significant enhancement of cardiovascular and motor responses evoked by normally innocuous brushing of the hair (hair deflection), as compared to responses evoked by either hair deflection after i.t. saline (SAL), or to i.t. STR (40 micrograms) with no tactile stimulus. The present study investigated: (1) the pharmacology of afferent neural inputs involved in STR-dependent allodynia using neonatal capsaicin and the non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX); and (2) the effect of i.t. STR on responses evoked by peripheral noxious stimulation. Neonatal capsaicin (25 mg/kg, s.c., post-natal day (PND) 1, and 50 mg/kg, s.c., PND 2, 3, 4, 11, 25, 55 and 85) significantly attenuated the responses evoked by noxious mechanical, thermal or chemical stimuli, but had no effect on STR-dependent allodynia. All hair deflection-evoked, STR-dependent responses were dose-dependently inhibited by i.t. NBQX. The ED50 values and 95% confidence intervals were 10.4 micrograms (5.5-19.6) for the motor withdrawal response, 14.4 micrograms (8.6-24.0) for changes in MAP and 12.2 micrograms (6.8-21.8) for changes in HR. Cortical EEG synchrony was unchanged by i.t. NBQX confirming its spinal locus of action. Intrathecal STR neither reduced nor enhanced the responses elicited by noxious stimuli in capsaicin- or vehicle-pretreated rats. These results indicate that STR-dependent allodynia is initiated by primary afferents not normally involved in nociception (possibly A beta-fibers), and that STR-sensitive modulation in the spinal cord is selective for non-noxious sensory input. The sensitivity of STR-dependent allodynia to non-NMDA receptor antagonists, and the failure of i.t. STR to produce hyperalgesia to mechanical, thermal or chemical noxious stimuli, confirm the independence of nociceptive pathways and STR-sensitive afferent inputs in this model.

Production of 5α-Reduced Neurosteroids Is Developmentally Regulated and Shapes GABAAMiniature IPSCs in Lamina II of the Spinal Cord

“…In the adult spinal cord, antagonists of GlyR or GABA A R induce hyperexcitability of dorsal horn neurons and behavioral states characteristic of hyperalgesia and allodynia (Yaksh, 1989;Sherman and Loomis, 1996;Sorkin and Puig, 1996;Ishikawa et al, 2000). As shown in our experiments, the adult spinal cord has preserved a neurosteroidogenic potential and endogenously produced 5␣-reduced neurosteroids are able to efficiently increase the level of synaptic inhibition.…”

“…In the dorsal horn of spinal cord, synaptic inhibition mediated by GABA A receptors (GABA A Rs) and glycine receptors (GlyRs) is of fundamental importance to prevent the generation of hyperalgesia or allodynia (Yaksh, 1989;Sherman and Loomis, 1996;Sorkin and Puig, 1996). In lamina II, local excitatory and inhibitory interneurons receive and integrate cutaneous nociceptive messages conveyed by nonmyelinated (type C) primary afferent fibers before transmitting them to supraspinal centers (Millan, 1999).…”

C-fiber activity-dependent maturation of glycinergic inhibition in the spinal dorsal horn of the postnatal rat

“…The absence of glycine inhibition is likely to be a major contributor to the excitability of the neonatal dorsal horn and in particular to the strength of myelinated A-fiber-evoked responses, which are normally under strong glycinergic control in the adult (13,18,33). A-fiber inputs dominate neonatal dorsal horn activity before the second postnatal week (1,5,34) and Aβ fibers form a greater number of monosynaptic inputs to superficial dorsal horn neurons during the first weeks of life relative to Cfiber input (5,34).…”

“…Glycinergic transmission is also postnatally regulated (6) but remains to be investigated in neonatal dorsal horn circuits. In adults, Aβ fibers synapse directly onto glycinergic interneurons (11, 12) and glycine receptor (GlyR) antagonists enhance dorsal horn cell sensitivity to A-fiber inputs (13,14), analogous to that seen in the healthy developing neonate. We therefore hypothesized that the cutaneous sensitivity of neonates arises from an absence of glycinergic inhibition in the newborn dorsal horn.…”

The Inhibitory Neuronal Circuit of Spinal Cord in Neuropathic Pain

“…Glycine neurons mediate translaminar synaptic input to PKCγ interneurons of inner lamina II (6,18). PKCγ interneurons, which contain gamma isoform of protein kinase C, express glycine receptors GlyR α3 subunit and receive the inhibitory output of glycine neurons and the excitatory output of low-threshold Aβ-fiber (31,67). As PKC interneurons receive two types of input, excitatory postsynaptic potentials (EPSPs) from Aβ-fiber and inhibitory postsynaptic potential (IPSPs) from glycine neurons, a biphasic response was evoked in PKCγ + cells after using dorsal root (DR) stimulation (6).…”