ReviewNeuronal nicotinic receptors as analgesic targets: It's a winding road
Graphical abstract
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.)
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These authors contributed equally to this work.