Nerve injury increases an excitatory action of neuropeptide Y and Y2-agonists on dorsal root ganglion neurons

doi:10.1016/S0306-4522(98)00443-6

Neuroscience

Volume 89, Issue 1, March 1999, Pages 43-60

https://doi.org/10.1016/S0306-4522(98)00443-6 Get rights and content

Abstract

Damage to sensory nerves invokes the expression of neuropeptide Y in the cell bodies of sensory neurons in dorsal root ganglia. We therefore compared the action of this peptide on control dorsal root ganglia neurons with its action on neurons from animals in which the sciatic nerve had been cut. Neuropeptide Y (0.1–1.0 μM) increased the excitability of 24% of control neurons and its effect was stronger and more cells (56%) were affected after axotomy. Increased excitability was mediated via a Y₂-receptor and resulted from attenuation of Ca²⁺-sensitive K⁺-conductance(s) secondary to suppression of N-type Ca²⁺ channel current. Y₁-agonists potentiated L-type Ca²⁺ channel current in control neurons without altering excitability. This Y₁-effect was attenuated whereas effects mediated via Y₂-receptors were enhanced after axotomy. No evidence was found for involvement of Y₄- or Y₅-receptor subtypes in the actions of neuropeptide Y either on control or on axotomized dorsal root ganglion neurons.

It is concluded that neuropeptide Y increases the excitability of sensory neurons by interacting with a Y₂-receptor and thereby decreasing N-type Ca²⁺ channel current and Ca²⁺-sensitive K⁺-conductance(s). When peripheral nerves are damaged, dorsal root ganglion neurons start to express neuropeptide Y and its excitatory Y₂-excitatory effects are enhanced. The peptide may therefore contribute to the generation of aberrant sensory activity and perhaps to the etiology of injury-induced neuropathic pain.

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Citation Excerpt :
In contrast to the cellular localization of Y1 receptors, spinal Y2 receptors are located on primary afferent terminals [6]. Because axotomy increases Y2-mediated inhibition of Ca2+ channel currents in dorsal root ganglion neurons [2], and NPY attenuates excitatory post-synaptic currents in substantia gelatinosa cells via presynaptic Y2 receptors [27], we suggest that NPY acts at presynaptic Y2 receptors to inhibit the release of pronociceptive neurotransmitters. One such neurotransmitter could be glutamate, since Y2 agonists inhibit glutamate release from spinal synaptosomes [24].
Our previous work indicates that the intrathecal administration of neuropeptide Y (NPY) acts at its cognate receptors to reduce behavioral signs of nociception in several models of inflammatory pain, including the formalin test. The present study extends these findings to a rat model of peripheral neuropathic pain, and then evaluates the hypothesis that NPY inhibits inflammation- and nerve injury-induced activation of spinal nociceptive transmission. Here we show that NPY dose-dependently reduced behavioral signs of mechanical and cold hypersensitivity in the spared nerve injury (SNI) model. Intrathecal administration of either a Y1 (BIBO3304) or a Y2 (BIIE0246) receptor antagonist dose-dependently reversed the anti-allodynic actions of NPY. To monitor the effects of NPY on the stimulus-induced activation of spinal nociresponsive neurons, we quantified protein expression of the immediate-early gene c-fos in lamina I–VI of the L4–L5 dorsal horn, with special attention to the mediolateral pattern of Fos immunohistochemical staining after SNI. Either tactile stimulation of the hindpaw ipsilateral to nerve injury, or intraplantar injection of noxious formalin, increased the number of Fos-like immunoreactive profiles. Tactile stimulation evoked a mediolateral pattern of Fos expression corresponding to the innervation territory of the uninjured (sural) nerve. We found that intrathecal NPY reduced both formalin- and SNI-induced Fos expression. NPY inhibition of SNI-induced Fos expression was localized to the sural (uninjured) innervation territory, and could be blocked by intrathecal BIBO3304 and BIIE0246. We conclude that NPY acts at spinal Y1 and Y2 receptors to reduce spinal neuron activity and behavioral signs of inflammatory or neuropathic pain.

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Nerve injury increases an excitatory action of neuropeptide Y and Y2-agonists on dorsal root ganglion neurons

Abstract

Neuroscience

Trends Neurosci.

Neuroscience

Neuron

Neurosci. Lett.

Trends pharmac. Sci.

Neurosci. Lett.

Expl Neurobiol.

Neurosci. Lett.

Brain Res.

Brain Res.

Axotomy increases the sensitivity of rat sensory neurones to Y2 agonists

Br. J. Pharmac.

Ectopicα2-adrenoceptors couple to N-type Ca2+ channels in axotomized rat sensory neurons

J. Neurosci.

Chemically-mediated cross excitation in rat dorsal root ganglia

J. Neurosci.

Response of cutaneous sensory units with unmyelinated fibres to noxious stimuli

J. Neurophysiol.

Neuropeptide Y2 inhibits Ca2+ influx into cultured dorsal root ganglion neurones of the rat via a Y2 receptor

Br. J. Pharmac.

Actions of neuropeptide Y on the electrophysiological properties of nerve cells

Modulation of activity in dorsal root ganglion neurons by sympathetic activation in nerve-injured rats

J. Neurophysiol.

Cross excitation in dorsal root ganglia of nerve injured rats

J. Neurophysiol.

Nerve injury increases an excitatory action of neuropeptide Y and Y₂-agonists on dorsal root ganglion neurons

Axotomy increases the sensitivity of rat sensory neurones to Y₂ agonists

Ectopicα₂-adrenoceptors couple to N-type Ca²⁺ channels in axotomized rat sensory neurons

Neuropeptide Y₂ inhibits Ca²⁺ influx into cultured dorsal root ganglion neurones of the rat via a Y₂ receptor