Pregabalin as a Pain Therapeutic: Beyond Calcium Channels

Abstract

PHARMACOLOGY AND PROTEIN INTERACTIONS OF PREGABALIN Pregabalin Is a High-Affinity α2δ Subunit Ligand The alpha-2-delta (α2δ) subunits were first described as auxiliary subunits of the high voltageactivated calcium channels and are encoded by four genes: α2δ1, α2δ-2, α2δ-3 and α2δ-4. α2δ-1-3 are expressed in neurons as well as heart and skeletal muscle tissue (Gong et al., 2001), whereas α2δ-4 is found in non-neuronal cell types such as the retina and endocrine tissues (Dolphin, 2013). Pregabalin selectively binds to the α2δ-1 and α2δ-2 subunits and despite its original design as a GABA mimetic, pregabalin does not affect GABA A or GABA B receptor activity (Li et al., 2011). Interestingly, α2δ-1 expression appears to co-localize mainly with excitatory neurons whereas α2δ-2 is found largely in inhibitory neurons (Cole et al., 2005). Recently, it has been shown that gabapentin exerts differential effects on putative excitatory and inhibitory spinal dorsal horn neurons (Alles et al., 2017). It is thus possible that pregabalin has different effects on excitatory compared to inhibitory neurons through a mechanism involving α2δ-1 and α2δ-2 subunits. This distinction may represent an important pregabalin-mediated therapeutic action since excitationinhibition imbalance occurs in the spinal cord and brain in chronic pain states such as diabetic neuropathy and chronic pain accompanying multiple sclerosis (

Brain circuits for pain and its treatment

“…These features separate opioids from other common analgesic drugs that limit the production of pronociceptive mediators [for example, non-steroidal anti-inflammatory drugs (NSAIDs) (249)] or affect the function of primary afferent nociceptors (including sodium channel or calcium channel blockers such as lidocaine and ziconotide, respectively) or for which the molecular and circuit mechanisms of action remain unclear (such as gabapentinoids, anticonvulsants, and antidepressants). For example, activation of the gabapentin receptor 2-1, in addition to its effects on ion channels (250,251), can promote excitatory synaptogenesis in response to thrombospondin released by astrocytes in the SC DH (252,253). Gabapentin blocks this synaptogenesis mechanism, which may contribute to central sensitization during chronic neuropathic pain.…”

Efficacy of pregabalin as a monotherapy versus combined pregabalin and milnacipran in the management of fibromyalgia

“…The Food and Drug Administration (FDA) has approved 3 drugs for the treatment of FM: pregabalin (PGB), duloxetine, and milnacipran (MLN) 5 . PGB, a ligand for the α2‐δ subunit of voltage‐gated calcium channels, is thought to decrease the transmission of nociceptive signals via ascending pain pathways by modulating the calcium‐dependent release of excitatory neurotransmitters such as glutamate and substance P. Hence, this drug is used to decrease pain and improve sleep 6 . Duloxetine and MLN are dual reuptake inhibitors which are proposed to increase norepinephrine and serotonin signaling in the descending pain pathways, resulting in inhibition of pain signaling in the CNS 7 .…”

Neuropathic pain: Spotlighting anatomy, experimental models, mechanisms, and therapeutic aspects

“…They are able to inhibit the influx of calcium ions into the cell and thereby modulate neurotransmission. This mechanism of action is suggested to also decrease the hyperexcitability caused by neuropathic pain, discussed in Section 6.1 (recently reviewed in Alles et al, 2020). Kopel and Browner (2020) suggest the administration of pregabalin to patients which do not respond to gabapentin treatment.…”