Antinociceptive effects of the stereoisomers of nicotine given intrathecally in spinal rats

Nicotinic agonists display a wide-range profile of antinociceptive activity in acute, tonic, and chronic pain models. However, their effectiveness is limited by their unacceptable side effects. We investigated the antinociceptive effects of two new ␣4␤2* nicotinic partial agonists, varenicline and sazetidine-A, in acute thermal and tonic pain mouse models. Both drugs failed to induce significant effects in the tail-flick and hot-plate tests after subcutaneous administration. However, they blocked nicotine's effects in these tests at very low doses. In contrast to acute pain tests, varenicline and sazetidine-A dose-dependently induced an analgesic effect in the mouse formalin test after systemic administration. Their antinociceptive effects were mediated, however, by different nicotinic acetylcholine receptor (nAChR) subtypes. Sazetidine-A effects were mediated by ␤2* nAChR subtypes, whereas varenicline actions were attributed to ␣3␤4 nAChRs. Moreover, low inactive doses of varenicline blocked nicotine's actions in phase II of the formalin test. Overall, our results suggest that the antagonistic actions of varenicline at low doses are mediated by ␤2*-nAChRs and at higher doses as an agonist by ␣3␤4*-nAChRs. In contrast, both actions of sazetidine-A are mediated by ␤2*-nAChR subtypes. These results suggest that nicotinic partial agonists possess analgesic effects in a rodent tonic pain model and may provide a potential treatment for the treatment of chronic pain disorders.

Section: Introductionmentioning

confidence: 99%

The Antinociceptive Effects of Nicotinic Partial Agonists Varenicline and Sazetidine-A in Murine Acute and Tonic Pain Models

AlSharari

Carroll

McIntosh

et al. 2012

“…It is generally agreed that central pathways modulate the analgesic actions of nicotine (Sahley and Berntson, 1979); in particular, the spinal cord is a major site of action for tail-flick nociception given that i.t. administration of nicotinic agonists produces antinociception in this test (Aceto et al, 1986;Christensen and Smith, 1990). In addition, Caggiula et al (1995) suggested that nicotine's effects on the tail-flick and hot-plate tests involve at least partially separate pathways.…”

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confidence: 99%

Genetic Approaches Identify Differential Roles for α₄β₂^*Nicotinic Receptors in Acute Models of Antinociception in Mice

Damaj¹,

Fonck²,

Marks³

et al. 2007

The effects of nicotine on the tail-flick and hot-plate tests were determined to identify nicotinic receptor subtypes responsible for spinally and supraspinally mediated nicotine analgesia in knockin mice expressing hypersensitive ␣ 4 nicotinic receptors (L9ЈS), in seven inbred mouse strains (C57BL/6, DBA/2, A/2, CBA/2, BALB/ cByJ, C3H/HeJ, and 129/SvEv), and in two F1 hybrids (B6CBAF1 and B6D2F1). L9ЈS heterozygotes were ϳ6-fold more sensitive to the antinociceptive effects of nicotine than the wild-type controls in the hot-plate test but not in the tail-flick assay. Large differences in the effects of nicotine were also observed with both tests for the seven mouse strains. A/J and 129 mice were 6-to 8-fold more sensitive than CBA and BALB mice. In addition, B6CBAF1 hybrid mice were even less sensitive than CBA mice. Nicotinic binding sites were measured in three spinal cord regions and the hindbrain of the inbred strains. Significant differences in cytisine-sensitive, high affinity [

“…There is strong evidence that the antinociceptive effect of nicotine can occur via activation of nAChRs expressed in the central nervous system and peripheral sensory neurons (Aceto et al, 1986;Iwamoto, 1989;Christensen andSmith, 1990, 1991;Iwamoto and Marion, 1993;Flores et al, 1996;Khan et al, 1997;Bitner et al, 1998;Damaj et al, 1998). The antinociceptive effect of nicotine is of short duration (5-45 min) and occurs at relatively high doses (0.5-2 mg/kg).…”

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confidence: 99%

Effect of Dextrometorphan and Dextrorphan on Nicotine and Neuronal Nicotinic Receptors: In Vitro and in Vivo Selectivity

Damaj¹,

Flood²,

Ho³

et al. 2004

The effects of dextrometorphan and its metabolite dextrorphan on nicotine-induced antinociception in two acute thermal pain assays after systematic administration were evaluated in mice and compared with that of mecamylamine. Dextrometorphan and dextrorphan were found to block nicotine's antinociception in the tail-flick and hot-plate tests with different potencies (dextrometorphan is 10 times more potent than its metabolite). This blockade was not due to antagonism of N-methyl-D-aspartate receptors and/or interaction with opiate receptors, since selective drugs of these receptors failed to block nicotine's analgesic effects. Our results with the tail-flick and hot-plate tests showed an interesting in vivo functional selectivity for dextrometorphan over dextrorphan. In oocytes expressing various neuronal acetylcholine nicotinic receptors (nAChR), dextrometorphan and dextrorphan blocked nicotine activation of expressed ␣ 3 ␤ 4 , ␣ 4 ␤ 2 , and ␣ 7 subtypes with a small degree of selectivity. However, the in vivo antagonistic potency of dextrometorphan and dextrorphan in the pain tests does not correlate well with their in vitro blockade potency at expressed nAChR subtypes. Furthermore, the apparent in vivo selectivity of dextrometorphan over dextrorphan is not related to its in vitro potency and does suggest the involvement of other mechanisms. In that respect, dextrometorphan seems to behave as another mecamylamine, a noncompetitive nicotinic receptor antagonist with a preferential activity to ␣ 3 ␤ 4 * neuronal nAChR subtypes.Dextrometorphan is structurally related to the morphinan opioid levorphanol and is widely known as a centrally acting non-narcotic antitussive agent. Although dextromethorphan produces little analgesia by itself, it was found to potentiate the antinociceptive effects of opiates and reduce tolerance and physical dependence to morphine (Mao et al., 1996). In addition, Glick et al. (2001) have shown that both dextrometorphan and its major metabolite, dextrorphan, decreased nicotine, methamphetamine, and morphine self-administration in rats after s.c. administration. These multiple pharmacological and behavioral effects may be related to the ability of dextrometorphan and dextrorphan to interact with various receptor systems. Dextrometorphan has little or no opioid activity but binds with high affinity to sites (Klein and Musacchio, 1989). It binds, along with dextrorphan, with low affinity to the phencyclidine site of the NMDA receptor with dextrorphan having a 10-fold higher affinity at the site (Franklin and Murray, 1992). In addition, dextrometorphan and dextrorphan are both antagonists at NMDA glutamate receptors (Murray and Leid, 1984). They were also recently shown to block ␣ 3 ␤ 4 neuronal nicotinic receptors in a noncompetitive fashion (Hernandez et al., 2000) with dextrometorphan 3-fold less potent than dextrorphan. These reports suggest that dextrometorphan and/or dextrorphan may hold promise for understanding nicotine pharmacology and nicotine dependence. However, further st...