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

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.