The effect of intravenous lidocaine on brain activation during non-noxious and acute noxious stimulation of the forepaw: a functional magnetic resonance imaging study in the rat

Abstract

Background: Lidocaine can alleviate acute as well as chronic neuropathic pain at very low plasma concentrations in humans and laboratory animals. The mechanism(s) underlying lidocaine's analgesic effect when administered systemically is poorly understood but clearly not related to interruption of peripheral nerve conduction. Other targets for lidocaine's analgesic action(s) have been suggested, including sodium channels and other receptor sites in the central rather than peripheral nervous system. To our knowledge, the effect of lidocaine on the brain's functional response to pain has never been investigated. Here, we therefore characterized the effect of systemic lidocaine on the brain's response to innocuous and acute noxious stimulation in the rat using functional magnetic resonance imaging (fMRI).

Methods: Alpha-chloralose anesthetized rats underwent fMRI to quantify brain activation patterns in response to innocuous and noxious forepaw stimulation before and after IV administration of lidocaine.

Results: Innocuous forepaw stimulation elicited brain activation only in the contralateral primary somatosensory (S1) cortex. Acute noxious forepaw stimulation induced activation in additional brain areas associated with pain perception, including the secondary somatosensory cortex (S2), thalamus, insula and limbic regions. Lidocaine administered at IV doses of either 1 mg/kg, 4 mg/kg or 10 mg/kg did not abolish or diminish brain activation in response to innocuous or noxious stimulation. In fact, IV doses of 4 mg/kg and 10 mg/kg lidocaine enhanced S1 and S2 responses to acute nociceptive stimulation, increasing the activated cortical volume by 50%-60%.

Conclusion: The analgesic action of systemic lidocaine in acute pain is not reflected in a straightforward interruption of pain-induced fMRI brain activation as has been observed with opioids. The enhancement of cortical fMRI responses to acute pain by lidocaine observed here has also been reported for cocaine. We recently showed that both lidocaine and cocaine increased intracellular calcium concentrations in cortex, suggesting that this pharmacological effect could account for the enhanced sensitivity to somatosensory stimulation. As our model only measured physiological acute pain, it will be important to also test the response of these same pathways to lidocaine in a model of neuropathic pain to further investigate lidocaine's analgesic mechanism of action.

Figure 1

Outline of experimental stimulation paradigm. The rat was allowed to rest 6–10 min between each forepaw simulation trial. For the 2 mA experiment the stimulation time was 30 s. For the 4 mA and 8 mA currents the stimulation time was 9 s and 3 s, respectively. Lidocaine was injected IV after establishment of a functional magnetic resonance imaging (fMRI) baseline obtained over the first 1 h (4 set of stimulations). The first lidocaine dose was 1 mg/kg, the second dose 4 mg/kg, and the third 10 mg/kg. One hour was allowed between each of the escalating doses of lidocaine.

Figure 2

The time course of the average plasma lidocaine concentration after 1 mg/kg and 10 mg/kg in 3 rats. As can be seen, the plasma lidocaine concentration is at the “therapeutic” target range of >1 μg/mL at the 5-, 15-, and 25-min time points after the 10 m/kg lidocaine dose. For the 1 mg/kg dose the plasma concentration is <1 μg/mL at both the 5-min and 35 min time point.

Figure 3

Blood-oxygen-level-dependent (BOLD) activation maps of the 4 responses to 2 mA forepaw stimulation for 30 s obtained during control conditions (no lidocaine) derived from EPI magnetic resonance imaging (MRI) images in a Group 1 rat. The activated pixels were calculated using a cross-correlation of r >0.3 (STIMULATE). The color bar to the right is a 10-step transition from red to yellow which corresponds to a positive BOLD signal increase from 1% to 10%. In this particular animal the total volume of pixels with statistically significant BOLD signal increase over the 4 individual baseline stimulation trials was 3.6 mm³, 1.9 mm³, 3.6 mm³, and 2.4 mm³. The corresponding BOLD signal amplitudes of the 1st, 2nd, 3rd, and 4th stimulation was 2.3%, 2.1%, 4.8% and 2.4%, respectively.

Figure 4

(A) Brain activation map during forepaw stimulation with 8 mA for 3 s obtained under control conditions before the lidocaine challenges. In this particular animal, brain regions with statistically significant blood-oxygen-level-dependent (BOLD) signal increases was observed contralateral to the forepaw stimulated in the following regions: primary somatosensory cortex (S1), secondary somatosensory cortex (S2), hippocampus, posterior hypothalamus and ventral tegmental area (VTA). Thalamic activity was also observed ipsilateral to the forepaw stimulated. (B) Example with additional activation of the insula region in another rat. Th = thalamus; PH = posterior hypothalamus; Hip = hippocampus. Activated brain regions were identified by comparing locations on the raw EPI images with their anatomical counterparts and labeled rat brain atlas templates. BOLD signal changes are also observed outside of the brain corresponding to the surface of the brain and/or muscles and are related to large venous structures. In both A and B the color bar to the right is a 10-step transition from red to yellow which corresponds to a positive BOLD signal increase from 1% to 10%.

Figure 5

The result of a control experiment using the repetitive 8 mA, 3 s forepaw stimulation paradigm as outlined in Figure 1 but without the IV lidocaine challenges. As can be seen the amplitude of the blood-oxygen-level-dependent (BOLD) signal response measured in primary somatosensory cortex (average of all activated pixels) for each stimulation trial was relatively stable over the 2–3 h study time. The corresponding cortical volume activated by the 8 mA, 3 s forepaw stimulus in S1 for each trial was also relatively consistent over time although some variation is seen.

Figure 6

Brain activation patterns in response to the noxious 8 mA forepaw stimuli at baseline and 5-min after 4 mg/kg and 10 mg/kg IV lidocaine. As can be seen brain regions involved in nociception are still activated including S1 and S2 in spite of the lidocaine. In addition Figure 4 shows that the functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) response in S1/S2 is enhanced (increased total number of pixels) after administration of lidocaine. The color bar to the right is a 10-step transition from red to yellow which corresponds to a positive BOLD signal increase from 1% to 10%.

Figure 7

Brain activation patterns in response to the nociceptive stimulus 5-min after 10 mg/kg lidocaine in 2 different rats. In the first rat, (left forepaw stimulation) brain activation is elicited contralateral in the right in S1, ventral tegmental area (VTA), thalamus, and posterior hypothalamus. In the second rat (right forepaw stimulation) brain activation was elicited in the left S1/S2 and thalamus. The color bar to the right is a 10-step transition from red to yellow which corresponds to a positive blood-oxygen-level-dependent (BOLD) signal increase from 1% to 10%.