Endogenous opioids suppress activation of nociceptors by sub-nanomolar nicotine.
1. Nicotine can activate primary afferent nociceptors, one result of which is to increase neurogenic plasma extravasation. In this study we have demonstrated a novel proinflammatory effect of sub-nanomolar nicotine, mediated by peripheral action at sensory neurons. This action is normally masked by adrenal medulla-derived delta-opioid receptor agonists. 2. While neurogenic plasma extravasation in the knee joint of the rat was not increased by intra-articular perfusion of nicotine (10(-8) M), perfusion of nicotine, at concentrations as low as 10(-10) M, combined with naloxone to block opioid receptors (or naltrindole to block delta-opioid receptors) was able to enhance bradykinin-induced plasma extravasation. This pro-inflammatory effect of intra-articular nicotine was mimicked by subcutaneous nicotine which was abolished by intra-articularly-administered hexamethonium, a nicotinic receptor antagonist. 3. Following denervation of the adrenal medulla, intra-articular nicotine, alone at 10(-8) M, enhanced plasma extravasation, which was no longer enhanced by naloxone. 4. Destruction of primary afferents by neonatal treatment with capsaicin or blockade of sensory neurotransmitter by neurokinin-1 receptor antagonist RP-87,580 abolished the pro-inflammatory effect of nicotine. 5. The effect of nicotine we describe in promoting inflammation is exerted at extremely low concentrations and therefore could have relevance to smokers, patients receiving medicinal nicotine as therapy and even second-hand smokers. Since receptor mechanisms on peripheral terminals of nociceptors may also be present on central terminals, actions of the endogenous nicotinic agonist acetylcholine, at central terminals of primary afferents or at other sites in the central nervous system, may be similarly modulated by opioids.
Miao
F J
FJ
Department of Oral and Maxillofacial Surgery, University of California-San Francisco, San Francisco, CA 94143, USA. fjmiao@itsa.ucsf.edu
Benowitz
N L
NL
Levine
J D
JD
D000313:Adrenal Medulla / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001920:Bradykinin / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018738:Hexamethonium / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007719:Knee Joint / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects*; D018847:Opioid Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D009292:Narcotic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D018847:Opioid Peptides; D018040:Receptors, Neurokinin-1; D011957:Receptors, Opioid; D009270:Naloxone; D018738:Hexamethonium; D009271:Naltrexone; D009538:Nicotine; C055382:naltrindole; D002211:Capsaicin; D001920:Bradykinin