Local Anesthetic Inhibits Hyperpolarization-Activated Cationic Currents

Meng, Qingtao; Liu, Jin; Bayliss, Douglas A.; Chen, Xiangdong

doi:10.1124/mol.110.070227

Cited by 35 publications

(34 citation statements)

References 38 publications

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“…In addition to the best known activity as a use-dependent Na + channel blocker, lidocaine and its main metabolite inhibit hyperpolarization-activated and cyclic nucleotidegated (HCN) channels that contribute to pacemaker currents [58]. Lidocaine can also directly activate TRPV1 and modulate activation by capsaicin [59].…”

Section: Secondary Pharmacodynamics and Po-tential Common Mechanisms mentioning

confidence: 99%

Effects of Topical Capsaicin on Cutaneous Innervation: Implications for Pain Management

Bley¹

2013

TOPAINJ

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Changes in cutaneous innervation are a hallmark of neuropathic pain syndromes. Although in few cases the density of cutaneous innervation increases in painful areas, for the most part the density of nociceptive sensory nerve endings decreases and the degree of deinnervation seems to correlate with the severity of pain. In combination with tests for nociceptor function, immunostaining for protein gene product 9.5 (PGP 9.5) is commonly used as diagnostic tool to indicate these pathophysiological changes in cutaneous innervation. However, sole reliance on PGP 9.5 may underestimate the presence of regenerating sensory nerve terminals or fail to capture changes in the expression of proteins such as ion channels or receptors. Topical capsaicin consistently reduces intra-epidermal nerve fiber density assayed via PGP 9.5, and also increases thresholds for activation of some thermoreceptors. The mechanism of action involves a highly localized insult to cutaneous nociceptors mediated by activation of TRPV1 and calcium overload, and perhaps even a direct toxicity to mitochondria. It is possible that topical capsaicin and lidocaine share an ability to reduce cutaneous innervation by inducing localized toxicity in mitochondria-rich nociceptive terminals. Overall, the high local concentrations of drugs and even excipients delivered by topical analgesics into the skin may be able to activate secondary pharmacodynamic processes. Optimizing topical formulations of capsaicin or other analgesics to maximize pain relief with the fewest adverse effects is not a simple matter of varying drug concentration, and it is highly questionable whether ‘bioequivalence’ could ever be based simply upon equivalent cutaneous drug delivery.

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Section: Secondary Pharmacodynamics and Po-tential Common Mechanisms mentioning

confidence: 99%

Effects of Topical Capsaicin on Cutaneous Innervation: Implications for Pain Management

Bley¹

2013

TOPAINJ

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“…This observation is in contrast that a minimal common molecular architecture is shared among these channel types. [25][26][27][28][29] However, the recent appearance of bacterial sodium channel structures represents a significant step toward the long-held goal of structure-based drug design in sodium channels. The pharmacological and functional commonalities shared between bacterial and eukaryotic channels have been, thus far, limited by lack of detailed information on bacterial gating and pharmacological parameters.…”

Section: The Putative La-binding Sites Are Not Conserved In Nachbacmentioning

confidence: 99%

Molecular and functional determinants of local anesthetic inhibition of NaChBac

2012

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In our recent publication, we describe the local anesthetic (LA) inhibition of the prokaryotic voltage gated sodium channel NaChBac. Despite the numerous functional and putative structural differences with the mammalian sodium channels, the data show that LA compounds effectively and reversibly inhibit NaChBac channels in a concentration range similar to resting blockade on eukaryotic Navs. In addition to current reduction, LA application accelerated channel inactivation kinetics of NaChBac which could be accounted for in a simple state-model whereby local anesthetics increase the probability of entering the inactivated state. We have further explored what state (or states) local anesthetic blockade of NaChBac could pertain to eukaryotic sodium channels, and what molecular similarities exist between these disparate channel families. Here we show that the rate of recovery from inactivation remains unaffected in the presence of local anesthetics. Further, we show that two sites that support use-dependent inhibition in eukaryotic channels, do not affect block to the same extent when mutated in NaChBac channels. The data indicate that the molecular determinants and the inherent mechanisms for LA block are likely to be divergent between bacterial and eukaryotic Navs, but future experiments will help define possible similarities.

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“…Furthermore, commonly used local anesthetics such as lidocaine have been found to interact with a large spectrum of receptors and/or ion channels, such as potassium channels, 22 calcium channels, 23 TRPV1 channels, 24 and HCN channels 17,25 at clinical relevant concentrations. Thus, other molecular targets such as HCN channels might also contribute to the regional anesthetic effect of lidocaine.…”

Section: Discussionmentioning

confidence: 99%