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. 2001 May;133(1):23-8.
doi: 10.1038/sj.bjp.0704031.

Endogenous opioids suppress activation of nociceptors by sub-nanomolar nicotine

F J Miao  1 , N L Benowitz, J D Levine
Affiliations

Endogenous opioids suppress activation of nociceptors by sub-nanomolar nicotine

F J Miao et al. Br J Pharmacol. 2001 May.

Abstract

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.

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Figures

Figure 1
Figure 1
(A) Effect of intra-articular nicotine (10−8 M) and naloxone (10−5 M) on BK-induced PE. Co-perfusion of naloxone and nicotine enhanced BK-induced PE (•, n=6). In contralateral knees, nicotine alone decreased BK-induced PE (○, n=6). BK (160 ng ml−1) alone showed stable PE over time (X, n=8). Naloxone alone had no effect (data not shown). In all figures, the upper dashed line represents the average level of PE induced by BK at plateau (i.e., X) while the lower one the maximal decrease in BK-induced PE after intra-articular nicotine at 10−8 M (i.e., half-filled circles in Figure 1B). n: number of experiments performed. (B) Effect of de-afferentation on nicotine (10−8 M)-induced inhibition of BK-induced PE and the enhancement of BK-induced PE by nicotine administered with naloxone (10−5 M). After acute bilateral transection of sciatic and saphenous nerves, naloxone plus nicotine could still enhance BK-induced PE (▪, n=6). Half-filled circles represents nicotine-induced suppression of BK-induced PE in the absence of naloxone in nerve-intact animals (n=10). (C) Effect of naltrindole (a δ-opioid receptor antagonist) on intra-articular nicotine (10−8 M)-induced inhibition of BK-induced PE. In naltrindole (10−5 M, intra-articularly)-treated rats, nicotine enhanced BK-induced PE (⊠, n=8), similar to that in naloxone-treated rats (•, n=8). (D) Effect of adrenal denervation on intra-articular nicotine (10−8 M)-induced inhibition of BK-induced PE. Adrenal denervation did not affect the level of BK-induced PE (X, n=8). Compared to adrenal-intact rats receiving intra-articular nicotine (lower dashed line), the increase in BK-induced PE by nicotine in adrenal denervated rats is significantly enhanced (▴, n=6). Addition of intra-articular naloxone did not cause further enhancement (△, n=6).
Figure 2
Figure 2
(A) Effect of naloxone on sub-nanomolar nicotine-induced inhibition of BK-induced PE. Co-perfused with naloxone (10−5 M), nicotine (10−10 M) enhanced BK-induced PE (•, n=8). In contralateral knees, nicotine generated a decrease in BK-induced PE (○, n=8). (B) In rats treated neonatally with capsaicin, intra-articular treatment with nicotine (10−8 M) and naloxone (10−5 M) is no longer able to enhance BK-induced PE (▿, n=8) compared to normal rats (•, n=8). (C) Effect of RP-67,580 (a neurokinin-1 receptor antagonist; 10−7 M, intra-articularly) on intra-articular nicotine (10−8 M)-induced inhibition of BK-induced PE. In the presence of naloxone (10−5 M), intra-articular RP-67,580 significantly attenuated the effect of nicotine (10−8 M) in enhancing BK-induced PE (▾, n=8) without affecting the response in the contralateral control knee (▿, n=8). In the presence of naloxone, nicotine enhanced BK-induced PE (•, n= 8). (D) Effect of hexamethonium (a nicotinic receptor antagonist) on nicotine (10−5 mg kg−1, s.c.)-induced inhibition of BK-induced PE. Intra-articular hexamethonium (10−5 M) abolished the enhancement of BK-induced PE produced by systemic nicotine and naloxone (10−5 M, intra-articularly) (△, n=6), without affecting the enhancement in the contralateral knees not perfused with hexamethonium (▴, n=6).
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