Identification of the α ₂ -δ-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin

Abstract

Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics such as nonsteroidal antiinflammatory drugs or narcotics, these agents have no frank antiinflammatory actions and no effect on physiological pain. Although extensive preclinical studies have led to a number of suggestions, until recently their mechanism of action has not been clearly defined. Here, we describe studies on the analgesic effects of pregabalin in a mutant mouse containing a single-point mutation within the gene encoding a specific auxiliary subunit protein (␣2-␦-1) of voltage-dependent calcium channels. The mice demonstrate normal pain phenotypes and typical responses to other analgesic drugs. We show that the mutation leads to a significant reduction in the binding affinity of pregabalin in the brain and spinal cord and the loss of its analgesic efficacy. These studies show conclusively that the analgesic actions of pregabalin are mediated through the ␣2-␦-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.

Voltage-Gated Calcium Channel Antagonists: Potential Analgesics for Jejunal Pains

“…Prevention of nocifensive neurotrasmitters release by gabapentine and pregabaline occurs only during pathological processes, in which calcium channels are up-regulated and activated [40]. Both pregabaline and gabapentine are central analgesics [39]. Gabapentinoids inhibited visceral hypersensitivity in the experimental animals, as well as irritable bowel syndrome in humans [41].…”

“…Pregabalin and gabapentin bind with subtypes α 2δ in the cytoplasm and prevent calcium channels expression on the plasmatic membranes [38]. Preventing the binding and expression blocks calcium conductance and in consequence substance P (SP), calcitonin gene related peptide (CGRP) and glutamate cannot be released from primary afferent neurons [35,39]. Prevention of nocifensive neurotrasmitters release by gabapentine and pregabaline occurs only during pathological processes, in which calcium channels are up-regulated and activated [40].…”

Relative potency of pregabalin, gabapentin, and morphine in a mouse model of visceral pain

“…24 Similar slopes of dose-response curves do not necessarily indicate the existence of the same mechanisms of action, but it is already established that pregabalin and gabapentin exert their analgesic effect through the same site of action. 1,23 Although different slopes point to different mechanisms, the opposite is not true. Morphine has a different mechanism of action than gabapentinoids, but in the model studies, the dose-response relationships were parallel.…”

“…A least-square linear regression analysis of the log dose-response curves allowed the calculation of the dose that produced 20, 50, and 80% of effect (ED 20 , ED 50 , and ED 80 , respectively) with 95% confidence interval (CI) and respective equation, according to Motulsky's method. 1 Statistical analyses were done using the specialized software, GraphPad Prism 5 (GraphPad Software Inc., San Diego, CA, USA). A P value \ 0.05 was considered to indicate a statistically significant difference.…”

“…Their anticonvulsant and analgesic effects are attributed to their binding to the alpha-2-delta-1 subunit of voltage-dependent Ca-channels that decrease calcium influx and consequently decrease the release of the neurotransmitters norepinephrine, serotonin, and dopamine. 1 Pregabalin and gabapentin are prescribed in chronic pain states, such as post-herpetic neuralgia and diabetic peripheral neuropathy, 2 and they are used in complex pain syndromes such as fibromyalgia. 3 In addition, animal studies have shown that these drugs could have an analgesic effect in acute pain treatment.…”