Molecular pharmacology
-
Molecular pharmacology · Nov 2008
ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors.
Voltage-gated sodium (Na(V)1) channels play a critical role in modulating the excitability of sensory neurons, and human genetic evidence points to Na(V)1.7 as an essential contributor to pain signaling. Human loss-of-function mutations in SCN9A, the gene encoding Na(V)1.7, cause channelopathy-associated indifference to pain (CIP), whereas gain-of-function mutations are associated with two inherited painful neuropathies. Although the human genetic data make Na(V)1.7 an attractive target for the development of analgesics, pharmacological proof-of-concept in experimental pain models requires Na(V)1.7-selective channel blockers. ⋯ Mono-iodo-ProTx-II ((125)I-ProTx-II) binds with high affinity (K(d) = 0.3 nM) to recombinant hNa(V)1.7 channels. Binding of (125)I-ProTx-II is insensitive to the presence of other well characterized Na(V)1 channel modulators, suggesting that ProTx-II binds to a novel site, which may be more conducive to conferring subtype selectivity than the site occupied by traditional local anesthetics and anticonvulsants. Thus, the (125)I-ProTx-II binding assay, described here, offers a new tool in the search for novel Na(V)1.7-selective blockers.
-
Molecular pharmacology · Nov 2008
Muscarinic modulation of synaptic transmission via endocannabinoid signalling in the rat midbrain periaqueductal gray.
The midbrain periaqueductal gray (PAG) is involved in organizing behavioral responses to threat, stress, and pain. These PAG functions are modulated by cholinergic agents. In the present study, we examined the cholinergic modulation of synaptic transmission in the PAG using whole-cell voltage-clamp recordings from rat midbrain slices. ⋯ The carbachol inhibition of evoked EPSCs was also reduced in the combined presence of gallamine and AM251. These results indicate that M1 induced inhibition of GABAergic transmission within the PAG is mediated via endocannabinoids, which are produced via the phospholipase C/DAG lipase pathway and activate presynaptic cannabinoid CB(1) receptors. Thus, presynaptic muscarinic modulation of PAG function is mediated indirectly by M1 receptor-induced endocannabinoid signaling and directly by M2 receptors.