Peripheral nerve injury alters spinal nicotinic acetylcholine receptor pharmacology

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Abstract

Nicotinic acetylcholine receptors are widely expressed in the rat spinal cord and modulate innocuous and nociceptive transmission. The present studies were designed to investigate the plasticity of spinal nicotinic acetylcholine receptors modulating mechanosensitive information following spinal nerve ligation. A tonic inhibitory cholinergic tone mediated by dihydro-β-erythroidine- (DHβE) and methyllycaconitine- (MLA) sensitive nicotinic acetylcholine receptors was identified in the normal rat spinal cord and cholinergic tone at both populations of nicotinic acetylcholine receptors was lost ipsilateral to spinal nerve ligation. The administration of intrathecal nicotinic acetylcholine receptor agonists reduced mechanical paw pressure thresholds with a potency of epibatidine = A-85380 >> nicotine > choline in the normal rat. Following spinal nerve ligation, intrathecal epibatidine and nicotine produced an ipsilateral antinociception, but intrathecal A-85380 and choline did not. The antinociceptive response to intrathecal nicotine was blocked with the α7⁎ and α9α10⁎-selective nicotinic acetylcholine receptor antagonist, MLA, and the αβ heteromeric nicotinic acetylcholine receptor antagonist, DHβE. The antinociceptive effects of both intrathecal nicotine and epibatidine were mediated by GABAA receptors. Spinal [3H]epibatidine saturation binding was unchanged in spinal nerve-ligated rats, but spinal nerve ligation did increase the ability of nicotine to displace [3H]epibatidine from spinal cord membranes. Spinal nerve ligation altered the expression of nicotinic acetylcholine receptor subunits ipsilaterally, with a large increase in the modulatory α5 subunit. Taken together these results suggest that pro- and antinociceptive populations of spinal nicotinic acetylcholine receptors modulate the transmission of mechanosensitive information and that spinal nerve ligation-induced changes in spinal nicotinic acetylcholine receptors likely result from a change in subunit composition rather than overt loss of nicotinic acetylcholine receptor subtypes.

Introduction

A preponderance of behavioral evidence supports the importance of spinal nicotinic acetylcholine receptors in the transmission of nociceptive stimuli. Intrathecal administration of nicotinic acetylcholine receptor agonists increases blood pressure and heart rate, and produces agitation, nociceptive behaviors (e.g., vocalizations), and antinociception to thermal stimuli (Khan et al., 1994a, Khan et al., 1994b, Khan et al., 1997). Careful pharmacological studies conducted over the past several years have shown that different nicotinic acetylcholine receptor subtypes, located on distinct spinal structures, are responsible for each of these responses (Khan et al., 2001, Khan et al., 2004, Rashid and Ueda, 2002). Importantly, the nociceptive and antinociceptive responses can be attributed to different nicotinic acetylcholine receptor subtypes (Rueter et al., 2000).

In the rat central nervous system, eight α (α2–α7, α9–α10) and three β (β2–β4) subunits have been identified (Le Novere et al., 2002, Léna et al., 1999, Lips et al., 2002). Heterologous expression and knockout experiments have identified numerous heteropentameric combinations as well as some homopentameric combinations (α7, α9) of these subunits. The most prevalent nicotinic acetylcholine receptors in rat brain are the α4β2⁎ and α7⁎ receptors (the asterisk indicates the native subunit composition is unknown (Lukas et al., 1999, Marks et al., 1986). In contrast, spinal cord nicotinic acetylcholine receptors have been far less characterized. Radioligand binding studies support the presence of several distinct populations of nicotinic acetylcholine receptor subtypes in the spinal cord (Khan et al., 1997, Khan et al., 1994b).

In the spinal cord, nicotinic acetylcholine receptors are expressed on primary afferents (Genzen and McGehee, 2003, Miao et al., 2004, Roberts et al., 1995, Khan et al., 2004, Li et al., 1998), descending noradrenergic (Li et al., 2000) and serotoninergic (Cordero-Erausquin and Changeux, 2001) fibers presynaptically, as well as postsynaptically on spinal inhibitory and excitatory neurons (Cordero-Erausquin et al., 2004, Genzen and McGehee, 2005, Bradaia and Trouslard, 2002a, Bradaia and Trouslard, 2002b). Previous studies suggest that the α4β2⁎ and α7⁎ nicotinic acetylcholine receptors on primary afferent C-fibers are likely responsible for the nociceptive responses while an α3β4⁎ or a previously undescribed nicotinic acetylcholine receptor may be responsible for the antinociceptive properties (Khan et al., 2001, Rueter et al., 2000).

Peripheral nerve injury produces a variety of changes within the spinal cord both ipsilaterally and contralaterally, including changes in the expression of nicotinic acetylcholine receptors (Yang et al., 2004). Transection of the sciatic nerve greatly upregulates transcripts for the α5 and β2 nicotinic acetylcholine receptor subunits within the spinal cord dorsal horn (Yang et al., 2004). Spinal nerve ligation also increased the numbers of cells expressing the α3 subunit and the number of fibers expressing the α5 subunit (Vincler and Eisenach, 2004). The behavioral implications of injury-induced changes in spinal nicotinic acetylcholine receptors have not been investigated thoroughly. Partial sciatic nerve injury in the mouse results in an increased spinal antinociceptive potency of nicotinic agonists and a loss of cholinergic-stimulated GABAergic inhibitory tone at α4β2⁎ nicotinic acetylcholine receptors (Rashid and Ueda, 2002, Rashid et al., 2006). In the rat, tibial nerve transection results in a novel, antinociceptive effect of spinal nicotinic acetylcholine receptor agonists by increasing spinal glycinergic transmission (Abdin et al., 2006).

The current series of studies were undertaken to further examine the role of spinal nicotinic acetylcholine receptors modulating the transmission of nociceptive mechanical stimuli and to define injury-induced changes in nicotinic acetylcholine receptor function that may underlie changes in spinal nicotinic acetylcholine receptor pharmacology.

Section snippets

Animals

All animals used in this study were male Sprague–Dawley rats (200–250 g; Harlan, IN), housed in pairs prior to surgery and individually post-catheter implantation with free access to food and water. Protocols and procedures were approved by the Animal Care and Use Committee (Wake Forest University Health Sciences, Winston-Salem, NC).

Pro- and antinociceptive populations of spinal nicotinic acetylcholine receptors modulate the transmission of nociceptive mechanical stimuli

To assess the functionality of spinal nicotinic receptors in the modulation of mechanosensitive stimuli, normal rats were administered 2 commonly used nicotinic acetylcholine receptor antagonists intrathecally and paw withdrawal thresholds to mechanical pressure were measured. Baseline paw withdrawal thresholds ranged from 135 to 149 g and data were normalized to baseline paw withdrawal thresholds for each rat prior to drug administration. Both nicotinic acetylcholine receptor antagonists

Discussion

The results of these studies show that multiple populations of spinal nicotinic acetylcholine receptors function to facilitate and inhibit the transmission of nociceptive mechanical stimuli in the normal rat spinal cord. A variety of nicotinic acetylcholine receptor agonists reduced paw withdrawal thresholds in a dose-dependent manner while the nicotinic acetylcholine receptor antagonists DHβE and MLA blocked a tonic cholinergic antinociceptive tone within the normal rat spinal cord. Spinal

Acknowledgement

This work was supported by NIH grant R01 NS048158 (M.V.).

References (40)

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