Peripheral nerve injury alters spinal nicotinic acetylcholine receptor pharmacology

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 GABA A receptors. Spinal [ 3 H]epibatidine saturation binding was unchanged in spinal nerve-ligated rats, but spinal nerve ligation did increase the ability of nicotine to displace [ 3 H]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.

Relief of Hypersensitivity after Nerve Injury from Systemic Donepezil Involves Spinal Cholinergic and γ-Aminobutyric Acid Mechanisms

“…Consistent with our study, previous studies showed that intrathecal nicotinic receptor agonists increased withdrawal thresholds measured by paw pressure test in SNL animals. 14,27 In contrast, a previous study demonstrated that antiallodynic effect from orally administered donepezil is not affected by mecamylamine in SNL rats. 7 In normal animals, nicotinic receptors have no or little role on thermal antinociception from cholinesterase inhibition.…”

“…13,16,35 Stimulation of spinal nicotinic receptors has been reported to produce presynaptic GABA release and γ-aminobutyric acid type A receptor-mediated analgesia. 14,15,27,36 However, no previous study measured GABA concentrations in the spinal cord after stimulation of cholinergic receptors.…”

Systemic Administration of an Alpha-7 Nicotinic Acetylcholine Agonist Reverses Neuropathic Pain in Male Sprague Dawley Rats

“…2,46,67 We aimed to determine whether systemic administration of a novel selective α7 nAChR agonist, TC-7020, was also able to reverse CCI-induced neuropathic allodynia in both the ipsilateral and contralateral hind paws. CCI resulted in significant allodynic response compared with sham-treated rats, which was stable 10 days after surgery and throughout the remainder of the study in the vehicle group.…”

“…2,46,67 Choline, a naturally occurring nutritional supplement and a constituent of acetylcholine, is a selective α7 nAChR agonist. 50 Systemic administration of choline reduced hyperalgesia in the late phase of formalin 63 and was found to be effective in a rat model of postoperative pain.…”

The role of alpha5 nicotinic acetylcholine receptors in mouse models of chronic inflammatory and neuropathic pain

“…Interestingly, peripheral nerve injury greatly upregulated transcripts for the α 5 and β 2 nicotinic acetylcholine receptor subunits within the spinal cord dorsal horn [37]. In another study, spinal nerve ligation resulted in an increase of the expression of several nAChR subunits ipsilaterally, including α 5 subunit [38]. Taken together, these results suggest that α 5 *-nAChRs play an important role in changes in spinal connectivity (i.e., central sensitization) induced by nerve injury in rodents.…”