Nicotine Inhibits Voltage-Dependent Sodium Channels and Sensitizes Vanilloid Receptors

Abstract

. Nicotine is an alkaloid that is used by large numbers of people. When taken into the body, it produces a myriad of physiological actions that occur primarily through the activation of neuronal nicotinic acetylcholine receptors (nAChRs). We have explored its ability to modulate TRPV1 receptors and voltage-gated sodium channels. The reason for investigating nicotine's effect on sodium channels is to obtain a better understanding of its anti-nociceptive properties. The reasons for investigating its effects on capsaicin-activated TRPV1 channels are to understand how it may modulate this channel that is involved in pain, inflammation, and gustatory physiology. Whole cell patch-clamp recordings from rat trigeminal ganglion (TG) nociceptors revealed that nicotine exhibited anesthetic properties by decreasing the number of evoked action potentials and by inhibiting tetrodotoxin-resistant sodium currents. This anesthetic property can be produced without the necessity of activating nAChRs. Nicotine also modulates TRPV1 receptors inducing a several-fold increase in capsaicin-activated currents in both TG neurons and in cells with heterologously expressed TRPV1 receptors. This sensitizing effect does not require the activation of nAChRs. Nicotine did not alter the threshold temperature (ϳ41°C) of heat-activated currents in TG neurons that were attributed to arise from the activation of TRPV1 receptors. In this regard, its effect on TRPV1 receptors differs from those of ethanol that has been shown to increase the capsaicin-activated current but decrease the threshold temperature. These studies document several new effects of nicotine on channels involved in nociception and indicate how they may impact physiological processes involving pain and gustation.

TRPV1 Function in Mouse Colon Sensory Neurons Is Enhanced by Metabotropic 5-Hydroxytryptamine Receptor Activation

“…Several signaling pathways converge on TRPV1 to modulate its activity and, as shown in this and previous studies, alter neuron excitability (Bhave et al, 2003;Carr et al, 2003;Moriyama et al, 2003;Dai et al, 2004;Ferreira et al, 2004;Liu et al, 2004;Premkumar et al, 2004;Puntambekar et al, 2004). The potential role of TRPV1 in integrating different physical, chemical, and inflammatory signals and the comparatively high number of capsaicin-responsive colon sensory neurons support the relevance of this channel in sensation and visceral nociception.…”

Effects of Smoking on Neuropathic Pain in Two People With Spinal Cord Injury

“…Nicotine is known to act at nicotinic acetylcholine receptors that are located on peripheral nerves, in sympathetic ganglia, and in the central nervous system. Central administration of nicotinic acetylcholine receptor agonists has been noted to produce antinociceptive effects in both animals and humans (14,15), but peripheral administration of these same agonists can have pronociceptive effects (12) through mechanisms such as the sensitization of vanilloid receptors on primary afferent terminals (16). Increased sympathetic nervous system activity caused by direct ganglionic activation can also produce pain-modulatory effects.…”

Behavioral and neural responses to gustatory stimuli delivered non-contingently through intra-oral cannulas

“…That is, in all cases, the animals ingested tastants and water and for this reason we suggest that some of the tuning changes observed in all three protocols arise from evolving differences in the subjects' internals states over the course of each test session, in part due to processes involving feeding (sucrose, salt) and satiety. In this regard it has been shown that chemicals such as insulin [30,57], opiates [31], glucose [32,57] or glucagon [33] that are released throughout the feeding cycle may differentially affect taste responses throughout the gustatory axis.…”

“…We found that despite differences in behavioral responses in the three protocols tested, we observed similar and extensive inter-sequence variability in chemosensory GC responses. We attribute these chemical tuning changes to differences in areas of the oral cavity that are subjected to the tastants as the animals ingest or reject the tastants, and to changes in tuning properties that occur as a consequence of more central processes resulting from changes in the state of the animal [22] and to compounds that are released upon ingestion that can affect gustatory responses [30][31][32][33]57]. The experiment-wide probability of eliciting appetitive responses in each trial (solid lines) was plotted for both PRE and POST sequences (grey and black, respectively).…”