Elsevier

Biochemical Pharmacology

Volume 86, Issue 8, 15 October 2013, Pages 1208-1214
Biochemical Pharmacology

Review
Neuronal nicotinic receptors as analgesic targets: It's a winding road

https://doi.org/10.1016/j.bcp.2013.08.001Get rights and content

Abstract

Along with their well known role in nicotine addiction and autonomic physiology, neuronal nicotinic receptors (nAChRs) also have profound analgesic effects in animal models and humans. This is not a new idea, even in the early 1500s, soon after tobacco was introduced to the new world, its proponents listed pain relief among the beneficial properties of smoking. In recent years, analgesics that target specific nAChR subtypes have shown highly efficacious antinociceptive properties in acute and chronic pain models. To date, the side effects of these drugs have precluded their advancement to the clinic. This review summarizes the recent efforts to identify novel analgesics that target nAChRs, and outlines some of the key neural substrates that contribute to these physiological effects. There remain many unanswered mechanistic questions in this field, and there are still compelling reasons to explore neuronal nAChRs as targets for the relief of pain.

Introduction

The last two decades have seen an increase in the use of opioid drugs for the treatment of chronic non-cancer pain in the United States. Although opioid analgesics are highly efficacious [1], the associated side effects limit their usefulness [2]. In addition, opioids have high abuse liability [3]. Although the majority of chronic pain patients do not abuse prescription opioids [3], as noted by Compton and Volkow, the increases in opioid pain prescriptions and opioid abuse have been correlated [4]. Thus, there is a strong need for effective chronic pain treatments that lack the side effects of opioids.

Nicotinic acetylcholine receptors (nAChRs) may represent viable targets for novel analgesics. Although the pain-relieving properties of nicotinic acetylcholine receptors (nAChRs) are relatively recent findings, the link between nicotine and analgesia is not new. Oviedo y Valdes, a Spanish historian, first reported that tobacco relieved pain caused by syphilis in the early 16th century [5]. However, nicotine, a major constituent of tobacco, was not linked with analgesia until the 20th century when nicotine application was found to produce antinociception in cats [6]. More recent research has revealed that nicotine microinjection into various brainstem regions could be either pronociceptive or antinociceptive [7]. In addition, nicotine-induced antinociception can be blocked by mecamylamine, a nonselective neuronal nAChR antagonist [8]. The analgesic effect of nicotine has also been replicated in humans, as nicotine reduces acute pain experienced from a cold pressor test in both smokers and ex-smokers [9]. Although these findings supported developing nicotine as an analgesic, evidence showing its addictive effects raised concern [10], [11]. Furthermore, repeated administration of nicotine induces tolerance to antinociceptive effects in rats [12]. Despite these concerns, the focus on nAChRs as analgesic targets has become an active area of investigation.

In 1974, while conducting experiments in Ecuador, John Daly and Charles Myers found that a frog skin extract from Phyllobates anthonyi induces a Straub tail response, indicative of opioid expression in the extract [13], [14]. However, Daly later showed naloxone, an opioid antagonist, did not block the extract-induced Straub-tail response [13], [15]. Eventually the active compound, known as epibatidine [15], was isolated and subsequently shown to induce nAChR-mediated antinociception in rodents [16], [17]. Epibatidine is a nAChR agonist that binds to several nAChR subtypes, including α7, α4β2, and the neuromuscular α1β1δγ subtype [18]. Antinociceptive efficacy of epibatidine is similar to morphine with 100-fold higher potency in the hot-plate test [15]. Although epibatidine displays promising antinociceptive effects, it also induces adverse side effects, including dose-dependent decreases in body temperature and locomotor activity [16]. In addition, epibatidine increases blood pressure in rodents, which may show sensitization, as repeated administration can transform nonlethal doses into lethal doses [18]. The nonselective nAChR agonist properties of epibatidine raise the possibility that distinct subsets of nAChRs mediate its antinociceptive vs. adverse effects [19].

Section snippets

α4β2 nAChRs

Researchers at Abbott labs initially focused on α4β2 nAChR agonists with the goal of developing treatments for Alzheimer's disease [13], [14]. However, they discovered structural similarities between their candidate drugs and epibatidine [13]. This lead to the development of ABT-594 [13], a compound closely related to epitabidine, with higher selectivity for α4β2 nAChRs [19]. ABT-594 produces antinociception that is more potent than either nicotine or morphine, with equal or higher efficacy in

Neural substrates for nAChR-dependent analgesia

Despite the pharmacological and behavioral evidence supporting nAChR-mediated analgesia, remarkably little is known about its underlying cellular mechanisms. Nicotinic receptors are found along ascending as well as descending nociceptive pathways and have been especially well characterized in the spinal cord dorsal horn and in sensory nerve afferents. In addition to the spinal cord, supraspinal areas are also critical sites of action for nicotinic analgesics, yet we know even less about the

Conclusions

In summary, nAChRs mediate antinociception via various receptor subtypes distributed among multiple central and peripheral nociceptive areas. This diversity of neural substrates and nAChR subtypes provides a rich environment for analgesic drug development. This richness also carries cost, as unwanted side effects have sidelined some of the strongest candidate nicotinic analgesic drugs. Perhaps the combination of agonists with selective positive allosteric modulators will provide an efficacious

Acknowledgments

This work was supported by grants from the Frank Family Fellowship (I.U.) and the NIH DA07255 (C.D.), DA015918, and DA019695 (D.S.M.)

References (93)

  • J.E. Macor et al.

    The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective α7 nicotinic receptor partial agonist

    Bioorganic and Medicinal Chemistry Letters

    (2001)
  • L.M. Broad et al.

    PSAB-OFP, a selective α7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor

    European Journal of Pharmacology

    (2002)
  • M.A. Oatway et al.

    The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury

    Pain

    (2004)
  • S. Furst

    Transmitters involved in antinociception in the spinal cord

    Brain Research Bulletin

    (1999)
  • D. Bertrand et al.

    Allosteric modulation of nicotinic acetylcholine receptors

    Biochemical Pharmacology

    (2007)
  • K. Freitas et al.

    Ivy Carroll F, Lichtman AH, Imad Damaj M. Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models

    Neuropharmacology

    (2013)
  • R. Nirogi et al.

    Antinociceptive activity of α4β2* neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain

    European Journal of Pharmacology

    (2011)
  • J. Ji et al.

    A-366833: a novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane α4β2 nicotinic acetylcholine receptor selective agonist: Synthesis, analgesic efficacy and tolerability profile in animal models. Biochem

    Pharmacology

    (2007)
  • C.H. Lee et al.

    α4β2 neuronal nicotinic receptor positive allosteric modulation: an approach for improving the therapeutic index of α4β2 nAChR agonists in pain

    Biochemical Pharmacology

    (2011)
  • C.Z. Zhu et al.

    Potentiation of analgesic efficacy but not side effects: co-administration of an alpha4beta2 neuronal nicotinic acetylcholine receptor agonist and its positive allosteric modulator in experimental models of pain in rats

    Biochemical Pharmacology

    (2011)
  • G.R. Dube et al.

    Loss of functional neuronal nicotinic receptors in dorsal root ganglion neurons in a rat model of neuropathic pain

    Neuroscience Letters

    (2005)
  • M.A. Vincler et al.

    Knock down of the α5 nicotinic acetylcholine receptor in spinal nerve-ligated rats alleviates mechanical allodynia

    Pharmacology Biochemistry and Behavior

    (2005)
  • L.E. Rueter et al.

    Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain

    Pain

    (2003)
  • A.V. Osborne-Hereford et al.

    Neuronal nicotinic alpha7 receptors modulate inflammatory cytokine production in the skin following ultraviolet radiation

    Journal of Neuroimmunology

    (2008)
  • T.J. Rowley et al.

    Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain

    British Journal of Anaesthesia

    (2010)
  • K.S. Lips et al.

    Coexpression of α9 and α10 nicotinic acetylcholine receptors in rat dorsal root ganglion neurons

    Neuroscience

    (2002)
  • H. Peng et al.

    Characterization of the human nicotinic acetylcholine receptor subunit alpha (α) 9 (CHRNA9) and alpha (α) 10 (CHRNA10) in lymphocytes

    Life Sciences

    (2004)
  • A.T. Hama et al.

    The antinociceptive effect of intrathecal administration of epibatidine with clonidine or neostigmine in the formalin test in rats

    Pain

    (2001)
  • I.M. Khan et al.

    Nociceptive and antinociceptive responses to intrathecally administered nicotinic agonists

    Neuropharmacology

    (1998)
  • M.H. Rashid et al.

    Neuropathy-specific analgesic action of intrathecal nicotinic agonists and its spinal GABA-mediated mechanism

    Brain Research

    (2002)
  • M. Cordero-Erausquin et al.

    Nicotine differentially activates inhibitory and excitatory neurons in the dorsal spinal cord

    Pain

    (2004)
  • M.I. Damaj et al.

    The antinociceptive effects α7 nicotinic agonists in an acute pain model

    Neuropharmacology

    (2000)
  • J.R. Genzen et al.

    Nicotinic modulation of GABAergic synaptic transmission in the spinal cord dorsal horn

    Brain Research

    (2005)
  • M.H. Rashid et al.

    Tonic inhibitory role of α4β2 subtype of nicotinic acetylcholine receptors on nociceptive transmission in the spinal cord in mice

    Pain

    (2006)
  • I. Yalcin et al.

    Nociceptive thresholds are controlled through spinal β2-subunit-containing nicotinic acetylcholine receptors

    Pain

    (2011)
  • D. Takeda et al.

    Modulation of inhibitory synaptic activity by a non-α4β2, non-α7 subtype of nicotinic receptors in the substantia gelatinosa of adult rat spinal cord

    Pain

    (2003)
  • O. Dehkordi et al.

    Expression of alpha-7 and alpha-4 nicotinic acetylcholine receptors by GABAergic neurons of rostral ventral medulla and caudal pons

    Brain Research

    (2007)
  • B. Godinez-Chaparro et al.

    Secondary mechanical allodynia and hyperalgesia depend on descending facilitation mediated by spinal 5-HT(4), 5-HT(6) and 5-HT(7) receptors

    Neuroscience

    (2012)
  • E. Hamurtekin et al.

    Possible involvement of supraspinal opioid and GABA receptors in CDP-choline-induced antinociception in acute pain models in rats

    Neuroscience Letters

    (2007)
  • C.G. Baddick et al.

    An autoradiographic survey of mouse brain nicotinic acetylcholine receptors defined by null mutants

    Biochemical Pharmacology

    (2011)
  • A.P. Guimaraes et al.

    Antinociceptive effects of carbachol microinjected into different portions of the mesencephalic periaqueductal gray matter of the rat

    Brain Research

    (1994)
  • M. Nakamura et al.

    Presynaptic nicotinic acetylcholine receptors enhance GABAergic synaptic transmission in rat periaqueductal gray neurons

    European Journal of Pharmacology

    (2010)
  • J.C. Ballantyne et al.

    Efficacy of opioids for chronic pain: a review of the evidence

    Clinical Journal of Pain

    (2008)
  • A. Baldini et al.

    A review of potential adverse effects of long-term opioid therapy: a practitioner's guide

    Primary Care Companion for CNS Disorders

    (2012)
  • W.M. Compton et al.

    Major increases in opioid analgesic abuse in the United States: concerns and strategies

    Drug and Alcohol Dependence

    (2006)
  • C. Corti

    A history of smoking

    (2007)
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    These authors contributed equally to this work.

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