Elsevier

Physiology & Behavior

Volume 72, Issue 4, March 2001, Pages 567-573
Physiology & Behavior

Can conditioned histamine release occur under urethane anesthesia in guinea pigs?

https://doi.org/10.1016/S0031-9384(00)00438-8Get rights and content

Abstract

Many clinical and experimental data have shown that learning can occur under general anesthesia. To clarify this possibility with respect to allergic reactions, particularly asthmatic responses, we first established classical conditioned histamine release in response to a neutral odor by using pairings of the odor and an inhaled antigen for five sessions (Experiment 1) and then investigated whether conditioned histamine release into the plasma, bronchoalveolar lavage fluid (BALF), and lung tissue, which followed such a conditioning procedure, would be produced in urethane-anesthetized guinea pigs in the presence or absence of antigen (Experiment 2). Ovalbumin (OA) was used as the unconditioned stimulus (US) and dimethylsulfide (DMS) served as the conditioned stimulus (CS) in both experiments. In Experiment 1, the plasma histamine levels in the conditioned group increased significantly more than those of the unpaired control group in response to the CS during consciousness. In Experiment 2 in the absence of antigen, however, no significant differences in the histamine levels were found regarding the groups (DMS, triethylamine, saline, or unsensitized) or the time course (before, immediately, 5 min, and 10 min after the inhalations) during anesthesia, except for the finding that the histamine levels in the lung tissue specimens from the DMS group were significantly higher than those from the triethylamine group. In Experiment 2 in the presence of antigen, there was a significant increase in the plasma histamine levels after exposure to the US, irrespective of the presence of the CS, however, no significant difference in the histamine levels was observed between the US and the CS+US groups. These results indicated that a classically CS might not induce asthmatic responses under anesthesia.

Introduction

A clear interaction has been demonstrated between the central nervous system (CNS) and the peripheral immune functions, which communicate bidirectionally through several pathways, such as the autonomic nerves, hormones, and cytokines [1]. As evidence of the influence of the CNS on the immune functions, a large number of classical or Pavlovian conditioning effects on immunity have so far been identified [1]. Previous classically conditioned alterations include the conditioned release of several mediators in allergic reactions. Russell et al. [23] reported that histamine is released into the plasma in response to a neutral odor used for a classical conditioned regimen in which an immunological challenge is given in association with the odor in guinea pigs. In addition, evidence of mucosal mast cell/nerve interactions in the intestinal lamina propria of rats has been demonstrated [4], and rat mast cell protease II, a specific enzyme in thymus-dependent mast cells in the mucosal lamina propria of the intestine and lung, has also been observed to be released in response to audiovisual cues as conditioned stimuli (CS) [15].

Classically conditioned phenomena seem to be related to memory formation during consciousness. Hippocampal damage has been suggested to impair trace conditioning [6], [18]. However, classically conditioned responses may not necessarily require consciousness, because conditioning phenomena have also been reported in a dog after the removal of the neocortex [5] and in cats treated with a complete lower brainstem transection [19].

One methodological approach to investigate the role of consciousness in classical conditioned responses is to use anesthetic agents. Several researchers have attempted to clarify whether classical conditioned phenomena can be found even under general anesthesia, however, the findings were contradictory [9], [11]. For example, a few researchers have reported that classical conditioning effects were found in rats anesthetized with ketamine [7], in sheep anesthetized with pentobarbitone sodium and halothane [21], and in mice anesthetized with halothane [20]. Conversely, other studies failed to show such findings [10], [25]. To our knowledge, however, no classical conditioning of chemical mediators involved in the allergic processes has yet been investigated in the anesthetized state. Although it is well known that many anesthetic agents induce histamine release, which is important for allergic responses [8], [14], [16], urethane has not yet been reported to affect histamine release [12]. As a result, urethane seems to be suitable for the study of conditioning of allergic responses during anesthesia.

As for the classical conditioning paradigm, previous studies have been made regarding the effect of various instructions during general anesthesia on postanesthetic behavior or physiological parameters [7], [10], [20], [21], [25]. On the other hand, there is little data on whether behavioral or physiological parameters, which were acquired during a state of consciousness, can be reproduced under general anesthesia. Although auditory stimuli, such as spoken suggestions and tone, have been used as CS under general anesthesia in many studies [7], [10], [20], [25], other stimuli, including odors, have so far been scarcely applied.

The present study was conducted to investigate the role of consciousness on the retention of a conditioned allergic, particularly asthmatic, response previously acquired during a state of consciousness. In the first experiment, we present data indicating a conditioned histamine release during consciousness using an odor as a CS in the guinea pig, i.e. a model of bronchial asthma. In the second experiment, we aimed to examine whether such an odor-associated histamine release, which was established in a conscious state, could be reproduced under general anesthesia in the presence or absence of antigen. We hypothesized that a conditioned allergic response might be reproduced during anesthesia, because asthmatic attacks tend to occur either in the middle of the night or very early in the morning during sleep, a decreased state of consciousness [2], and the skin response to histamine is able to be modified by hypnosis in a state of altered consciousness [13].

Section snippets

Subjects

Hartley male guinea pigs (Seiwa Experimental Animal Institute; Fukuoka, Japan), 8 weeks old at the start of the experiments, were used. The animals were housed in standard laboratory cages. The cages were kept in a soundproof, air-conditioned holding room at the animal research facility at the university, with an ambient temperature of 23±1°C and 65±5% humidity. A 12:12 light/dark schedule (lights on at 07:00 h) with ad libitum access to food and water was maintained throughout the experiments.

Sensitization

Experiment 1

There were significant differences in the plasma histamine levels regarding the between-subjects effects of the groups [F(1,18)=4.94, P<.05] and the within-subjects effects of the time course [F(1,18)=30.83, P<.01; Fig. 1]. The plasma histamine levels showed a significant elevation after the inhalation of DMS alone in comparison to those of the baseline. The CS–US group displayed significantly higher levels of plasma histamine than did the CS/US group. In addition, significant interactions

Discussion

The present study was carried out to investigate the possibility of allergic reactions occurring during general anesthesia using a classical conditioning paradigm in guinea pigs. We examined whether odor-associated histamine release, which was established in a conscious state, could be reproduced under general anesthesia. To go ahead with the study, we first demonstrated that conditioned histamine release, in which an immunological challenge was paired with the presentation of a neutral odor,

Acknowledgements

We thank Prof. Masato Ikeda (Department of Occupational Health Economics, University of Occupational and Environmental Health) for his help in the statistical analysis.

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    1

    Present address: Institute for Occupational Health Science, Aichi Medical University, 21 Karimata, Yamako, Nagakute-cho, Aichi 480-1195, Japan.

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