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. May-Jun 2019;10(3):209-224.
doi: 10.32598/bcn.9.10.180. Epub 2019 May 1.

Acute Tramadol-Induced Cellular Tolerance and Dependence of Ventral Tegmental Area Dopaminergic Neurons: An In Vivo Electrophysiological Study

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Acute Tramadol-Induced Cellular Tolerance and Dependence of Ventral Tegmental Area Dopaminergic Neurons: An In Vivo Electrophysiological Study

Shabnam Khodayari et al. Basic Clin Neurosci. .
Free PMC article

Abstract

Introduction: Ventral Tegmental Area (VTA) is a core region of the brainstem that contributes to different vital bio-responses such as pain and addiction. The Dopaminergic (DA) cellular content of VTA has major roles in different functions. This study aims to evaluate the cellular effect of tramadol on the putative VTA-DA neurons.

Methods: Wistar rats were assigned into three groups of control, sham, and tramadol-treated. The animals were anesthetized and their VTA-DA neuronal activity was obtained under controlled stereotaxic operation. The firing rate of the neurons was extracted according to principal component analysis by Igor Pro software and analyzed statistically considering P<0.05 as significant. Tramadol (20 mg/kg) was infused intraperitoneally.

Results: Overall, 121 putative VTA-DA neurons were isolated from all groups. In tramadol-treated rats, the inhibition of the neuronal firing was proposed as tolerance and the excitation period as dependence or withdrawal. The Mean±SD inhibition time lasted up to 50.34±10.17 minutes and 31% of neurons stopped firing and silenced after 24±3 min on average but the remaining neurons lowered their firing up to 43% to 67% of their baseline firing. All neurons showed the excitation period, lasted about 56.12±15.30 min, and the firing of neurons increased from 176% to 244% of their baseline or pre-injection period.

Conclusion: The tolerance and dependence effects of tramadol are related to the changes in the neuronal firing rate at the putative VTA-DA neurons. The acute injection of tramadol can initiate neuroadaptation on the opioid and non-opioid neurotransmission to mediate these effects.

Keywords: Dependence; Dopamine; Firing rate; Tolerance; Tramadol; Ventral Tegmental Area.

Figures

Figure 1.
Figure 1.
A typical multiunit recording of the VTA Dopaminergic neurons in the control group A. A trace of the multiunit recording; B. A typical spike signature of VTA Dopaminergic neuron isolated from the recording. The VTA Dopaminergic neurons have commonly a three-phase extracellular spike shape with the firing rate less 10 spikes/second. The showed neuron had triphasic (+/−/+) shape with a notch at the beginning of the first + phase. The mean amplitude of the showed neuron was about 800 µV peak-to-peak. VTA Dopaminergic neurons showed a low spontaneous firing rate (<10 spikes/second).
Figure 2.
Figure 2.
A sample of the multiunit firing of the putative VTA Dopaminergic neurons in the control group A. A sample trace of the multiunit firing of the VTA Dopaminergic neurons in the control group; B. The histogram of the firing of the VTA Dopaminergic neurons of the control group. In the control group (naïve) animals, the VTA Dopaminergic neuronal firing under standard condition was recorded up to 120 min. The Mean±SD firing rate of the neurons in the control group was 4.4±0.61 spikes/second. The mean firing in each minute was calculated from the averaged firing in each second in every minute. The data are presented as Mean±SD.
Figure 3.
Figure 3.
The firing of the putative VTA Dopaminergic neurons in the sham group The tramadol vehicle (sterile normal saline) applied intraperitoneally, showing pre- and post-injection firing rate of the selected neurons evaluated. A. The firing of a sample of VTA Dopaminergic multiunit neurons in the sham group. In the sham groups, the putative VTA Dopaminergic neuronal firings were recorded under standard condition up to 120 min. The injection of the tramadol vehicle (sterile normal saline, in the 10th min) done by 30-gauge syringe; B. The histogram of the neuronal firing rate of the recorded neurons. Vehicle had no significant effect on the neuronal firing. The paired Student t-test was used for statistical analysis.
Figure 4.
Figure 4.
The histogram of the mean firing of a typical putative Ventral Tegmental Area Dopaminergic (VTA-DA) neuron after infusion of tramadol (20 mg/kg, single dose, IP, in the 10th minute) The pre- and post-injection neuronal firing were recorded until the last firing returned to the baseline of pre-injection one. The typical decrease or inhibition of firing and consecutive excitation were seen in the Figure. The recorded neuronal firing was obtained and averaged in 1 second in each minute with 1 ms bin size for the evaluation of pattern change. The pre-stimulus time histogram was compared between the pre- and post-injection to evaluate statistical significance. The recording of neuronal firing continued until the firing of post-injection period returned to the pre-injection period rate. In all recordings of tramadol treatment, neuronal firings showed two distinct phases in the firing rate. A short time after tramadol injection, the neuronal firing decreased. This period is called the inhibition period or neuronal tolerance. In the presented sample, the neuron was silent about 13 min and in the inhibition period, the Mean±SD of firing was 1.83±1.94 spikes/second. In this neuron, the duration of inhibition was 93 min. The second phase began with an increase in the firing rate as excitation or dependence period. The mean firing rate of the excitation period was 8.33±1.87 spikes/second and the maximum rate was 11.4 spikes/second. The duration of the excitation period was 87 min. The final Mean±SD baseline firing was 5.2±0.16 spikes/second. The firing rate of the baseline, inhibition, and excitation periods were significantly different (using 1-way analysis of variance, Tukey’s post-hoc test, P<0.001).
Figure 5.
Figure 5.
The bar chart of the firing rates of the putative Ventral Tegmental Area Dopaminergic (VTA-DA) neurons The chart shows the comparison of the averaged neuronal firing rate of the control and sham groups with the different periods of responses to tramadol injection (pre-injection, post-inhibition, post-excitation, and final baseline). Tramadol was injected in the 10th minute and the neuronal firings were obtained until the return of pre-injection firing rate. The mean firing rate of pre- and post-injection calculated for determination of the statistical difference. The Figure shows a significant statistical difference between pre- and post-injection of tramadol. The two distinct phases of tramadol effects (inhibition as tolerance and excitation as dependence) are seen in the firing rates of the neurons (using 1-way ANOVA, Tukey’s post hoc test, *** P<0.001).

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