Effects of naltrexone and histamine antagonists on the antinociceptive activity of the cimetidine analog SKF92374 in rats

doi:10.1016/S0006-8993(96)01288-7

Brain Research

Volume 748, Issues 1–2, 14 February 1997, Pages 168-174

https://doi.org/10.1016/S0006-8993(96)01288-7 Get rights and content

Abstract

A recent study showed that SKF92374, a structural analog of the histamine H₂ receptor antagonist cimetidine, induces antinociception after intraventricular (i.v.t.) administration in the rat. SKF92374 lacked significant activity on H₁ or H₂ receptors, but had weak activity on H₃ receptors. To test the hypothesis that SKF92374-induced antinociception is mediated by an action on H₃ receptors, the effects of the H₃ agonist R-α-methylhistamine (RAMH) and the H₃ antagonist thioperamide (both by i.v.t. administration) were investigated on SKF92374 antinociception. SKF92374-induced antinociception was slightly enhanced by thioperamide (30 μg), but unaffected by a range of doses of RAMH (up to 2 μg). Furthermore, SKF92374-induced antinociception was not reduced by large doses of systemically-administered antagonists of H₁ (pyrilamine), H₂ (zolantidine), H₃ (GT-2016), or opioid (naltrexone) receptors. These findings show that the novel compound SKF92374 induces antinociception by a non-opioid mechanism that does not utilize brain H₁, H₂ or H₃ receptors.

Introduction

Previous studies have established that histamine (HA) is an analgesic mediator in the central nervous system. Thus, HA induces antinociception after administration into the brain of rats and mice 6, 7, 12, 28, 31, 34, 35, 42. HA may play a role in opiate-induced or stress-induced analgesia because HA antagonists block morphine-induced antinociception 20, 21, 22, 40and naloxone-resistant footshock-induced antinociception 14, 19. Both H₁ and H₂ antagonists have been shown to block antinociception produced by HA or HA agonists in the brain 6, 30, 35, 42. However, some H₂ antagonists such as cimetidine induce antinociception in the absence of exogenous HA 26, 29, 30, 33. Our previous study [27]showed that both cimetidine and a novel analog (SKF92374: N-cyano-N′-methyl-N″-(3-(4-imidazolyl)propyl)-guanidine) induce highly effective antinociception on the hot-plate and the tail-flick nociceptive tests following intracerebral and intraventricular (i.v.t.) microinjections in rats. More recently, it was shown (Li et al., submitted) that SKF92374 also induces antinociception on a mechanical nociceptive test (tail-pinch) in rats and on a thermal test (tail-immersion) in mice. Furthermore, at a dose inducing maximal antinociception, SKF92374 did not produce significant motor impairment on an accelerated rotarod test or modify spontaneous locomotor activity, suggesting a selective analgesic action (Li et al., submitted).

The mechanism of SKF92374 antinociception remains unknown. SKF92374 was slightly (1.6–1.8-fold) more potent than cimetidine, with no difference in slopes of the dose-response curves [27]. However, SKF92374 showed very weak activity (400-fold lower affinity than cimetidine) on H₂ bioassays. In addition, SKF92374 had no effect (up to 100 μM) on guinea pig ileum H₁ receptors and no effect (up to 10 μM) on rat brain HA N-methyltransferase activity, the predominant HA metabolizing enzyme. Thus, the antinociceptive effect of SKF92374 is unlikely to be mediated by a direct action on H₁ or H₂ receptors [27].

It is well accepted that H₃ receptors may act as brain autoreceptors to inhibit HA synthesis and release 2, 3. It has been reported that H₃ antagonists such as thioperamide increase HA release in several brain regions 4, 23, 41, whereas the H₃ agonist R-α-methylhistamine decreases brain HA release [1]. SKF92374 showed weak H₃ antagonism (K_d=5.2 μM) on both the guinea pig ileum bioassay and brain autoradiographic binding assays [27]. Although this H₃ affinity is not high, estimated concentrations of SKF92374 in the brain after antinociceptive doses could be large enough to act on H₃ receptors. Thus, SKF92374 might induce antinociception by blocking H₃ receptors, thereby increasing HA release. This hypothesis requires careful examination, since known H₃ antagonists have biphasic, sub-maximal effects on nociceptive tests 27, 28(also see Section 4).

In the present study, the effects of centrally-administered H₃ agonists and H₃ antagonists were examined on SKF92374 antinociception to test the hypothesis that this drug induces antinociception by acting on H₃ receptors. To further investigate the role of histaminergic mechanisms in SKF92374 antinociception, the effects of systemically-administered H₁, H₂ and H₃ antagonists were also studied on HA- and SKF92374-induced antinociception. Since previous studies found that HA antinociception is inhibited by opiate antagonists 6, 7, 34, we have also investigated the effect of the opiate antagonist naltrexone on both HA- or SKF92374-induced antinociception.

Section snippets

Animals

Male Sprague–Dawley rats (Taconic Farms, Inc., Germantown, NY; 230–320 g at the time of testing) were maintained on a reverse 12 h light/dark cycle (lights on at 19:00 h, lights off at 07:00 h). Food and water were freely available to these animals. Each animal was only used for a single experiment. All procedures were reviewed and approved by the AMC Institutional Animal Care and Use Committee.

Drugs and solutions

SKF92374, thioperamide and GT-2016 base were dissolved in HCl (1.0–1.2 N), titrated to a pH between

Open field observation of SKF92374-treated rats

Animals treated with up to 100 μg of SKF92374 i.v.t. showed no loss of consciousness or abnormal motor behavior. All treated subjects exhibited normal grooming, vibrasse movement and normal exploratory behavior.

Effects of the opiate antagonist naltrexone on SKF92374- and HA-induced antinociception

Based on previous dose-response and time course studies [27], i.v.t. doses of 30 μg of HA and 100 μg of SKF92374 at 10 min were chosen for further characterization. The effects of the long-acting opiate antagonist naltrexone (i.p., 30 min) were studied (Fig. 1). Neither SKF92374- nor

Discussion

Previous work has suggested that brain opiate receptors might mediate HA analgesia. For example, antinociceptive responses induced by i.v.t. HA were inhibited by the opiate antagonist naloxone in rats [6]and mice 7, 34. Since it was suspected that SKF92374 might be acting through a histaminergic mechanism, the possibility that SKF92374-induced antinociception might be mediated by opiate receptors was investigated presently. Thus, the effects of the long-acting opioid antagonist naltrexone were

Acknowledgements

This research was supported by NIDA Grant DA-03816.

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Improgan, a congener of the H₂ antagonist cimetidine, produces non-opioid antinociception which is blocked by the CB₁ antagonist rimonabant, implying a cannabinoid mechanism of action. Since cannabinoids produce hypothermia as well as antinociception in rodents, the present study investigated the pharmacological activity of improgan on core body temperature and nociceptive (tail flick) responses. Improgan (60, 100 and 140 μg, intraventricular [ivt]) elicited significant decreases in core temperature 3–30 min following injection with a maximal hypothermic effect of − 1.3 °C. Pretreatment with rimonabant (50 μg, ivt) produced a statistically significant but incomplete (29–42%) antagonism of improgan hypothermia. In control experiments, the CB₁ agonist CP-55,940 (37.9 μg, ivt) induced significant decreases in core temperature (− 1.8 °C) 3–30 min following injection. However, unlike the case with improgan, pretreatment with rimonabant completely blocked CP-55,940 hypothermia. Furthermore, CP-55,940 and improgan elicited maximal antinociception over the same time course and dose ranges, and both effects were attenuated by rimonabant. These results show that, like cannabinoid agonists in the rat, improgan produces antinociception and hypothermia which is blocked by a CB₁ antagonist. Unlike cannabinoid agonists, however, improgan does not produce locomotor inhibition at antinociceptive doses. Additional experiments were performed to determine the effect of CC12, a recently discovered improgan antagonist which lacks affinity at CB₁ receptors. Pretreatment with CC12 (183 μg, ivt) produced complete inhibition of both the antinociception and the hypothermia produced by improgan, suggesting the possible role of an unknown improgan receptor in both of these effects.
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Improgan is a non-opioid analgesic which does not act at known histamine or cannabinoid receptors. Because improgan antinociception is blocked by low doses of a cannabinoid CB₁ antagonist, the present experiments determined if development of cannabinoid tolerance in mice would alter improgan antinociception. Twice-daily injections of Δ⁹-tetrahydrocannabinol (THC, 10 mg/kg, s.c.) for 3.5 days induced 47–54% and 42–56% reductions in cannabinoid (WIN 55,212-2, 20 μg, i.c.v.) and improgan (30 μg, i.c.v.) antinociception, respectively, as compared with responses from vehicle-treated groups. Because improgan lacks cannabinoid-like side effects in rats, and does not act directly on cannabinoid CB₁ receptors, the finding that development of cannabinoid tolerance reduces improgan antinociception suggests that this drug may release endocannabinoids, or activate novel cannabinoid sites. Either possibility offers the potential for developing new types of analgesics.
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The antinociceptive profile of selected histamine H₂ and histamine H₃ receptor antagonists led to the discovery of improgan, a non-brain-penetrating analgesic agent which does not act on known histamine receptors. Because no chemical congener of improgan has yet been discovered which has both antinociceptive and brain-penetrating properties, the present study investigated the antinociceptive effects of a series of chemical compounds related to zolantidine, a brain-penetrating histamine H₂ receptor antagonist. The drugs studied presently contain the piperidinomethylphenoxy (PMPO) moiety, hypothesized to introduce brain-penetrating characteristics. Following intracerebroventricular (i.c.v.) dosing in rats, six of eight drugs produced dose- and time-related antinociception on both the tail flick and hot plate tests over a nearly eight-fold range of potencies. Ataxia and other motor side effects were observed after high doses of these drugs, but two of the compounds (SKF94674 and loxtidine) produced maximal antinociception at doses which were completely devoid of these motor effects. Consistent with the hypothesis that PMPO-containing drugs are brain-penetrating analgesics, SKF94674 and another derivative (JB-9322) showed dose-dependent antinociceptive activity 15 to 30 min after systemic dosing in mice, but these effects were accompanied by seizures and death beginning 45 min after dosing. Other drugs showed a similar pattern of antinociceptive and toxic effects. In addition, loxtidine produced seizures without antinociception, whereas zolantidine produced neither effect after systemic dosing in mice. Although several of the drugs tested have histamine H₂ receptor antagonist activity, neither the antinociception nor the toxicity was correlated with histamine H₂ receptor activity. The present results are the first to demonstrate the existence of brain-penetrating antinociceptive agents chemically related to zolantidine and improgan, but further studies are needed to understand the mechanisms of both the pain relief and toxicity produced by these agents.
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Research reportEffects of naltrexone and histamine antagonists on the antinociceptive activity of the cimetidine analog SKF92374 in rats