Biphasic modulation by galanin of excitatory synaptic transmission in substantia gelatinosa neurons of adult rat spinal cord slices

Abstract

Yue HY, Fujita T, Kumamoto E. Biphasic modulation by galanin of excitatory synaptic transmission in substantia gelatinosa neurons of adult rat spinal cord slices. J Neurophysiol 105: 2337-2349, 2011. First published March 16, 2011 doi:10.1152/jn.00991.2010.-Although intrathecally administrated galanin modulates nociceptive transmission in a biphasic manner, this has not been fully examined previously. In the present study, the action of galanin on synaptic transmission in the substantia gelatinosa (SG) neurons of adult rat spinal cord slices was examined, using the whole cell patch-clamp technique. Galanin concentration-dependently increased the frequency of spontaneous excitatory postsynaptic current (EPSC; EC 50 ϭ 2.0 nM) without changing the amplitude, indicating a presynaptic effect. This effect was reduced in a Ca 2ϩ -free, or voltage-gated Ca 2ϩ channel blocker La 3ϩ -containing Krebs solution and was produced by a galanin type-2/3 receptor (GalR2/R3) agonist, galanin 2-11, but not by a galanin type-1 receptor (GalR1) agonist, M617. Galanin also concentration-dependently produced an outward current at Ϫ70 mV (EC 50 ϭ 44 nM), although this appeared to be contaminated by a small inward current. This outward current was mimicked by M617, but not by galanin 2-11. Moreover, galanin reduced monosynaptic A␦-fiber-and C-fiber-evoked EPSC amplitude; the former reduction was larger than the latter. A similar action was produced by galanin 2-11, but not by M617. Spontaneous and focally evoked inhibitory (GABAergic and glycinergic) transmission was unaffected by galanin. These findings indicate that galanin at lower concentrations enhances the spontaneous release of L-glutamate from nerve terminals by Ca 2ϩ entry from the external solution following GalR2/R3 activation, whereas galanin at higher concentrations also produces a membrane hyperpolarization by activating GalR1. Moreover, galanin reduces L-glutamate release onto SG neurons from primary afferent fibers by activating GalR2/R3. These effects could partially contribute to the behavioral effect of galanin. pain; patch clamp; spinal dorsal horn GALANIN, a 29/30-amino acid peptide, was first extracted from porcine upper intestines in 1983 (Tatemoto et al. 1983). Subsequently, this peptide was reported to extensively exist in the peripheral and central nervous systems (CNS) (Lang et al. 2007). Recently, it was established that galanin serves as a neurotransmitter or neuromodulator in various physiological functions, including feeding and pain (Hökfelt 2005;Lang et al. 2007;Liu and Hökfelt 2002). There are three types of G protein-coupled metabotropic receptors (GalR1, GalR2, GalR3) for galanin (Lang et al. 2007).There is much evidence demonstrating that galanin plays a role in regulating nociceptive transmission to the spinal dorsal horn from the periphery. First, galanin-immunoreactivity, GalR1, GalR2, and GalR3 mRNAs and proteins exist in the rat The substantia gelatinosa (SG; lamina II of Rexed) of the spinal dorsal horn is thought to play an important role in ...

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…This effect appears to be mediated by GAL 2 , presumably located on terminals of primary afferents and DH neurons, because it is mimicked by low-dose galanin (2-11), but not the GAL 1 preferential agonist M617 (Yue et al, 2011). Conversely, it was demonstrated that galanin (2-11) decreases spontaneous EPSC frequency (Alier et al, 2008).…”

“…Ablation of primary afferent innervation into the spinal cord does not appear to significantly decrease galanin binding (indicative of galanin receptor expression/levels) in the spinal cord, suggesting galanin receptors are present mainly on postsynaptic neurons (Kar and Quirion, 1994;Zhang et al, 1998). However, more recent studies imply that galanin also functions presynaptically in the DH, likely via GAL 2 (Alier et al, 2008;Yue et al, 2011). It is noteworthy that galanin and galanin receptor binding have also been detected in monkey DRG and spinal cord (Zhang et al, 1993a(Zhang et al, , 1995a, and galanin is expressed in human DRG (Landry et al, 2003).…”

“…Conversely, it was demonstrated that galanin (2-11) decreases spontaneous EPSC frequency (Alier et al, 2008). Furthermore, galanin or galanin (2-11) both reduce nociceptor stimulation-evoked EPSC amplitudes, indicative of decreased primary afferent glutamate release (Alier et al, 2008;Yue et al, 2011). Galanin produces variable dose-dependent effects on postsynaptic currents in both excitatory and inhibitory lamina II neurons; GAL 1 agonism appears to predominantly cause hyperpolarization (Yue et al, 2011), and highdose galanin (2-11) decreases membrane excitability (Alier et al, 2008;Yue et al, 2011).…”

“…Furthermore, galanin or galanin (2-11) both reduce nociceptor stimulation-evoked EPSC amplitudes, indicative of decreased primary afferent glutamate release (Alier et al, 2008;Yue et al, 2011). Galanin produces variable dose-dependent effects on postsynaptic currents in both excitatory and inhibitory lamina II neurons; GAL 1 agonism appears to predominantly cause hyperpolarization (Yue et al, 2011), and highdose galanin (2-11) decreases membrane excitability (Alier et al, 2008;Yue et al, 2011). Overall, the effect of galanin in the spinal cord is likely to be determined by several factors, including the sensitivity of the receptors to galanin, the phenotype of the receptorbearing neurons (e.g., neurotransmitter content and electrophysiological properties), and the local circuitry in the DH.…”

The Inhibitory Neuronal Circuit of Spinal Cord in Neuropathic Pain

“…Galanin produced a biphasic dose-dependent effect on spinal nociceptive excitability. In pain processing, the activation of postsynaptic GAL1 extent anti-nociceptive actions with decrease membrane excitability of dorsal horn neurons at high doses, while the activation of presynaptic GAL2 media pro-nociceptive action at low doses (28,29). Spinal parvalbumin(PV) positive cells mainly distribute in lamina I-III.…”