Trends in Pharmacological Sciences
ReviewThe diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities?
Section snippets
Pregabalin
Pregabalin and gabapentin are specific ligands of the α2-δ auxiliary subunit of voltage-gated calcium channels that is expressed at presynaptic endings of neurons in the brain and spinal cord. Chemical structure/activity relationship studies with animal models [1] and experiments in transgenic mouse models show that binding of pregabalin at α2-δ subtype 1 (α2-δ-1) is necessary and likely to be sufficient to modulate nociception, anxiolytic-like action, and anticonvulsant action 1, 2, 3. They
Molecular and anatomical sites of action
Pregabalin and gabapentin are chemically and pharmacologically related amino acid drugs that are both used to prevent partial seizures of epilepsy and are also used to treat some kinds of neuropathic pain and other disorders. Despite chemical similarity to gamma-aminobutyric acid (GABA), pregabalin and gabapentin do not mimic GABA or act specifically at GABA receptors or GABA synapses [1]. Currently, no evidence indicates that relevant actions of pregabalin or gabapentin result from molecular
Action of pregabalin to treat epilepsy
Epileptic seizures entail abnormally synchronized neuronal activity that prevents normal function. Partial epilepsy is the most common type, affecting a small part of the brain, often in the neocortex or limbic system. Partial seizures may propagate and spread as they progress. By contrast, absence seizures are generalized from the start, affecting the neocortex and thalamus simultaneously. Seizures begin with hyperexcitability in both animal models [19] and human patients [20]. Pregabalin and
Action of pregabalin to reduce hyperalgesia, central sensitization, and chronic pain
Injuries to nerves often result in neuropathic pain, probably as a consequence of increased discharge to the CNS. Enhanced inputs can strengthen synapses and amplify nociceptive processing, a process termed ‘central sensitization’. This manifests in patients as pain along with sensory gain, which is reflected clinically in touch- or cold-induced ‘allodynia’ [28]. Sensitization of rat dorsal horn neurons is observed after peripheral nerve injury [29]. Injury-induced sensitization is mediated, in
Action of pregabalin to reduce anxiety
Anxiety disorders are characterized by the common symptoms of fear and worry, which are hypothetically linked to abnormal activation of the amygdala and its connections [45]. Preclinical data have linked the anxiolytic effects of pregabalin to required activity at the α2-δ-1 subunit using models of anxiety in mice [46]. In normal human volunteers, pregabalin reduces the activation of the amygdala and insula during anticipatory or emotional processing [47], analogous to the action of other
Action of pregabalin to reduce RLS
RLS is a relatively common sensory–motor neurological disorder characterized by the abnormal involuntary urge to move limbs, particularly the legs. Symptoms appear at rest and can worsen markedly at night. The paresthesias may be extremely discomforting and result in impaired sleep. Randomized and placebo-controlled clinical studies have documented the potential therapeutic benefit of pregabalin in patient populations expressing the primary symptoms of RLS [8]. However, it is not approved for
Action of pregabalin to enhance slow-wave sleep
Healthy sleep involves repeated sequences of different sleep stages [wakefulness, non-rapid eye movement (non-REM) sleep (stages 1, 2, 3, and 4), and REM sleep] [55]. Each is characterized by different firing patterns in the neocortex. Electroencephalography (EEG) studies distinguish between ‘fast’ delta waves that predominate during waking and REM sleep and ‘slow’ delta waves that predominate in slow-wave sleep (stages 3 and 4) [55]. Noradrenergic neurons (REM-off cells) originating from the
Pregabalin dose-related AEs
The two most common side effects of pregabalin, regardless of indication or use, are dizziness (or vertigo) and somnolence (or drowsiness) (http://labeling.pfizer.com/ShowLabeling.aspx?id=561). These AEs are usually dose related, are mild to moderate in intensity, occur soon after starting therapy, and often resolve over time. In some patients, dizziness and somnolence persist. In some trials, multiple doses of pregabalin were associated with occasional reports of peripheral edema, lazy eye,
Discussion
From increasing preclinical and clinical evidence, we suggest that the observed clinical effects of pregabalin may all result from drug action at the α2-δ protein in various circuits within the CNS. Several lines of evidence point to this conclusion, but as yet only one high-affinity molecular site of action has been identified. AEs associated with pregabalin also are likely to be caused by this molecular interaction.
The ability of pregabalin to subtly reduce the release of excitatory
Concluding remarks
In conclusion, we suggest that pregabalin does not target various diseases or anatomical areas per se. Instead, we suggest that several disorders (anxiety, epilepsy, pain, fibromyalgia, RLS, sleep interference) may share neuronal hyperactivity in various brain circuits that may be somewhat normalized by pregabalin acting at α2-δ protein targets.
Further study of drug actions at the α2-δ protein and the impact on the release of associated neurotransmitters and on network activity in several
Disclaimer statement
S.M.S. has served as a Consultant for Acadia, Astra Zeneca, Avanir, Biomarin, BristolMyers Squibb, Cenerex, Dey, Eli Lilly, Forest, GenoMind, GlaxoSmithKline, J&J, Jazz, Lundbeck, Merck, Neuronetics, Novartis, Noven, ONO, Orexigen, Otsuka, PamLabs, Pfizer, RCT Logic, Rexahn, Roche, Servier, Shire, Solvay, Sunovion, Trius, and Valeant. He has served on speakers’ bureaus for Arbor Scientia, Astra Zeneca, Eli Lilly, Forest, J&J, Merck, Neuroscience Education Institute, Pfizer, Servier, and
Acknowledgments
Medical writing support for the development of this manuscript was provided by Brenda Meyer of UBC Scientific Solutions and was funded by Pfizer Inc.
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2021, Brain, Behavior, and ImmunityCitation Excerpt :It was discovered that peripheral nerve injury upregulated presynaptic α2δ-1 expression and trafficking, which accounted for neuropathic pain development (Bauer et al., 2009; Hoppa et al., 2012; Zhou and David, 2013). It has been suggested that gabapentin and pregabalin interfere with anterograde trafficking of α2δ-1 from dorsal root ganglion neurons to the presynaptic terminals of the dorsal horns, resulting in reduced release of pain neurotransmitters such as glutamate and spinal sensitization, and subsequently attenuate neuropathic pain (Stahl et al., 2013; Hendrich et al., 2008). However, the gabapentinoids results are inconsistent with inhibition of Ca2+ currents, pain transmitter release and α2δ-1 upregulation and trafficking (Bauer et al., 2010; Chen et al., 2018; Bannister et al., 2011; Yang et al., 2014).
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