Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics

doi:10.1016/S0006-2952(99)00122-7

Biochemical Pharmacology

Volume 58, Issue 6, 15 September 1999, Pages 917-923

https://doi.org/10.1016/S0006-2952(99)00122-7 Get rights and content

Abstract

Pharmacological treatments for pain have come largely from two classes of compounds—the opioids and the nonsteroidal anti-inflammatory drugs (NSAIDs). Because of deficiencies associated with these two classes of compounds, exploration of novel approaches to pain relief has intensified of late. Nicotine, a neuronal nicotinic acetylcholine receptor (nAChR) agonist, has long been known to have antinociceptive effects in both experimental animals and humans. The relatively modest antinociceptive effects and the toxicities associated with nicotine preclude its development as an analgesic agent. However, recent discoveries in the nAChR field have stimulated interest in nAChR-targeted compounds as potential analgesic agents. Epibatidine, a potent nAChR agonist, was found to have full efficacy relative to opioids in preclinical pain models. Although epibatidine is toxic, these observations demonstrated that modest efficacy is not a general limitation of nAChR agonists. Moreover, exploration of the molecular biology of nAChRs revealed evidence of receptor diversity, suggesting that nAChR subtype-selective agents less toxic than nicotine might be discovered; and early medicinal chemistry efforts already have resulted in compounds with improved safety profiles. For example, ABT-594 is a nAChR agonist with the antinociceptive efficacy of epibatidine, but with an improved safety profile. This commentary reviews recent findings with nAChR-targeted compounds, explores potential mechanisms responsible for nAChR-mediated antinociception, and raises issues that must be addressed in developing compounds of this class as analgesics.

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Post-ictal antinociception is characterised by an increase in the nociceptive threshold that accompanies tonic and tonic-clonic seizures (TCS). The locus coeruleus (LC) receives profuse cholinergic inputs from the pedunculopontine tegmental nucleus. Different concentrations (1 μg, 3 μg and 5 μg/0.2 μL) of the muscarinic cholinergic receptor antagonist atropine and the nicotinic cholinergic receptor antagonist mecamylamine were microinjected into the LC of Wistar rats to investigate the role of cholinergic mechanisms in the severity of TCS and the post-ictal antinociceptive response. Five minutes later, TCS were induced by systemic administration of pentylenetetrazole (PTZ) (64 mg/kg). Seizures were recorded inside the open field apparatus for an average of 10 min. Immediately after seizures, the nociceptive threshold was recorded for 130 min using the tail-flick test. Pre-treatment of the LC with 1 μg, 3 μg and 5 μg/0.2 μL concentrations of both atropine and mecamylamine did not cause a significant effect on seizure severity. However, the same treatments decreased the post-ictal antinociceptive phenomenon. In addition, mecamylamine caused an earlier decrease in the post-ictal antinociception compared to atropine. These results suggest that muscarinic and mainly nicotinic cholinergic receptors of the LC are recruited to organise tonic-clonic seizure-induced antinociception.
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The dorsal raphe nucleus (DRN) is a key structure of the endogenous pain inhibitory system. Although the DRN is rich in serotoninergic neurons, cholinergic neurons are also found in that nucleus. Both ictal and inter-ictal states are followed by post-ictal analgesia. The present study investigated the role of cholinergic mechanisms in postictal antinociceptive processes using microinjections of atropine and mecamylamine, muscarinic and nicotinic cholinergic receptor antagonists, respectively, in the DRN of rats. Intraperitoneal injection of pentylenetetrazole (PTZ) (at 64 mg/kg) caused tonic and tonic-clonic seizures. The convulsive motor reactions were followed by an increase in pain thresholds, a phenomenon known as post-ictal analgesia. Pre-treatment of the DRN with atropine or mecamylamine at 1 µg, 3 µg and 5 µg/0.2 µL decreased the post-ictal antinociceptive phenomenon. The present results showed that the post-ictal analgesia was mediated by muscarinic and nicotinic cholinergic receptors in the DRN, a structure crucially involved in the neural network that organises post-ictal hypoalgesia.
α4β2* neuronal nicotinic receptor ligands (agonist, partial agonist and positive allosteric modulators) as therapeutic prospects for pain
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α4β2* neuronal nicotinic acetylcholine receptor are ligand-gated ion channels and widely expressed throughout the central and peripheral nervous system. α4β2* neuronal nicotinic acetylcholine receptor play crucial role in pain signaling via modulation of multiple neurotransmitters like acetylcholine, dopamine, γ-amino butyric acid (GABA) and norepinephrine. Both spinal and supraspinal pathways are involved in the mechanisms by which α4β2* neuronal nicotinic acetylcholine receptor ligands modulate the neuropathic and inflammatory pain. Selective α4β2* neuronal nicotinic acetylcholine receptor ligands are being developed for the treatment of neuropathic and inflammatory pain as they show considerable efficacy in a wide range of preclinical pain models. Agonists/partial agonists of α4β2* neuronal nicotinic acetylcholine receptor show efficacy in animal models of pain and their anti-nociceptive properties are blocked by nicotinic antagonists. Positive allosteric modulators are being developed with the aim to increase the potency or therapeutic window of agonists/partial agonists. Accumulating evidences suggest that anti-nociceptive effects of nicotinic acetylcholine receptor ligands may not be mediated solely by α4β2* neuronal nicotinic acetylcholine receptor. We have also reviewed the stage of clinical development of various α4β2* neuronal nicotinic acetylcholine receptor ligands.
Diazaspirocyclic compounds as selective ligands for the α4β2 nicotinic acetylcholine receptor
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Diazaspirocyclic ligands have been synthesized in four steps as selective α4β2 nicotinic acetylcholine receptor antagonists. Structural assignment of 1-(pyridin-3-yl)-2-spiropyrrolidino-3,2′-1-azabiclo[2.2.1]heptane 2, was confirmed using a combination of NMR experiments on a key intermediate, spirolactam 9. All three target compounds synthesized in this diazaspirocyclic series exhibited high affinity (K_i <35 nM) at the human α4β2 nAChR subtype, and very low affinity for the human α7, α3β4 (ganglion) and α1β1γδ (muscle) subtypes (K_i >500 nM).
A novel toxic alkaloid from poison hemlock (Conium maculatum L., Apiaceae): Identification, synthesis and antinociceptive activity
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2-Pentylpiperidine, named conmaculatin, a novel volatile alkaloid related to coniine was identified from the renowned toxic weed Conium maculatum L. (Apiaceae). The structure of conmaculatin was corroborated by synthesis (8 steps starting from cyclohexanol, overall yield 12%). Conmaculatin’s strong peripheral and central antinociceptive activity in mice was observed in a narrow dose range (10–20 mg/kg). It was found to be lethal in doses higher than 20 mg/kg.
Acetylcholine-mediated neurotransmission within the nucleus raphe magnus exerts a key role in the organization of both interictal and postictal antinociception
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Citation Excerpt :
Raphe–spinal pathways originating in the NRM reach the gelatinous substance of the spinal cord, inhibiting noxious inputs. Previous evidence has demonstrated that muscarinic and nicotinic receptors are involved in the control of perception of nociceptive stimuli in both animal trials and human models of pain [6,26]. Published reports have described the involvement of endogenous opioid receptors [11,12] in hypoalgesic processes following seizures.
The role of the acetylcholine-mediated system in the organization of postictal antinociception was investigated. For this purpose, nicotinic and muscarinic cholinergic receptor antagonists were microinjected into the nucleus raphe magnus (NRM), a key structure of the endogenous pain inhibitory system. After the tail-flick test baseline recording, male Wistar rats (N = 8 per group) were submitted to stereotaxic surgery for the introduction of a guide cannula aiming at the NRM. Five days after surgery, atropine or mecamylamine (1 µg/0.2 µL, 3 µg/0.2 µL, or 5 µg/0.2 µL) was microinjected into the NRM. The tail-flick withdrawal latency was recorded immediately after peripheral treatment with pentylenetetrazole (PTZ) (64 mg/kg), in two different interictal time windows, and for 130 minutes after the last seizure evoked by intraperitoneal injection of PTZ. The blockade of GABA-mediated Cl^– influx caused tonic–clonic convulsions in all animals followed by sustained postictal antinociception lasting 110 minutes after seizures; the nociceptive threshold was also found to be high in interictal periods. Pretreatment of the NRM with either atropine or mecamylamine antagonized both interictal and postictal antinociception, suggesting the involvement of cholinergic mechanisms recruiting muscarinic and nicotinic cholinergic receptors of the NRM in the organization of tonic–clonic seizure-induced antinociception.

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CommentariesTherapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics

Abstract

Trends Pharmacol Sci

Pharmacol Biochem Behav

J Biol Chem

Brain Res

Pharmacol Biochem Behav

Life Sci

Neuropharmacology

Brain Res

Eur J Pharmacol

J Physiol (Paris)

Neuropharmacology

Trends Neurosci

Brain Res

Pharmacol Biochem Behav

Opioid analgesics and antagonists

Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout

Pharmacology of neuropathic pain

Clin Neuropharmacol

Antidepressant drugs as treatments for chronic painEfficacy and mechanisms

New pharmacological strategies for pain relief

Annu Rev Pharmacol Toxicol

Visceral pain

Surg Gynecol Obstet

Antinociceptive effects of central and systemic administrations of nicotine in the rat

Psychopharmacology

Nicotine-induced antinociception in rats and miceCorrelation with nicotine brain levels

J Pharmacol Exp Ther

Antinociceptive action of nicotine and its methiodide derivatives in mice and rats

Br J Pharmacol

Epibatidine, a potent analgetic and nicotinic agonist

Mol Pharmacol

(±)-Epibatidine elicits a diversity of in vitro and in vivo effects mediated by nicotinic acetylcholine receptors

J Pharmacol Exp Ther

(±)-Epibatidine can differentially evoke responses mediated by putative subtypes of nicotinic acetylcholine receptors (nAChRs)

Med Chem Res

Neuronal nicotinic acetylcholine receptors as targets for drug discovery

J Med Chem

The molecular biology of neuronal nicotinic acetylcholine receptors

Crit Rev Toxicol

A subtype of nicotinic cholinergic receptor in rat brain is composed of α4 and β2 subunits and is up-regulated by chronic nicotine treatment

Mol Pharmacol

Commentaries
Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics