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 (α2-δ-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 α2-8-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 17537-17542 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 103 |
| Issue number | 46 |
| DOIs | |
| State | Published - Nov 14 2006 |
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ASJC Scopus subject areas
- Genetics
- General
Cite this
Identification of the α2-δ-1 subunit of voltage-calcium calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. / Field, Mark J.; Cox, Peter J.; Stott, Emma; Melrose, Heather L; Offord, James; Su, Ti Zhi; Bramwell, Steve; Corradini, Laura; England, Steven; Winks, Joanna; Kinloch, Ross A.; Hendrich, Jan; Dolphin, Annette C.; Webbl, Tony; Williams, Dic.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 46, 14.11.2006, p. 17537-17542.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of the α2-δ-1 subunit of voltage-calcium calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin
AU - Field, Mark J.
AU - Cox, Peter J.
AU - Stott, Emma
AU - Melrose, Heather L
AU - Offord, James
AU - Su, Ti Zhi
AU - Bramwell, Steve
AU - Corradini, Laura
AU - England, Steven
AU - Winks, Joanna
AU - Kinloch, Ross A.
AU - Hendrich, Jan
AU - Dolphin, Annette C.
AU - Webbl, Tony
AU - Williams, Dic
PY - 2006/11/14
Y1 - 2006/11/14
N2 - 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 (α2-δ-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 α2-8-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.
AB - 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 (α2-δ-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 α2-8-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.
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U2 - 10.1073/pnas.0409066103
DO - 10.1073/pnas.0409066103
M3 - Article
VL - 103
SP - 17537
EP - 17542
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 46
ER -