Preclinical assay of the effects of lacosamide, pregabalin, and tapentadol on the rat N1 spinal somatosensory evoked potential

: The high failure rate in translating novel analgesics into the clinic has highlighted the need for more translatable biomarkers of analgesic target engagement. The N13 component of spinal somatosensory evoked potential (SEP) has been proposed as a biomarker of spinal nociceptive processing in humans, but it is not known whether this can be back translated into rodents. Tapentadol, lacosamide, and pregabalin were used as pharmacological probes to assess the sensitivity of spinal SEPs to drug action. In anaesthetised, naïve rats (n = 44), a multielectrode silicon probe was inserted into the L4 spinal cord to record SEPs from the dorsal horn after electrical stimulation of the sciatic nerve. At baseline, the N1 component (rodent equivalent of the human N13) had an amplitude of 1.33 ± 0.07 mV at a latency of 4.6 ± 0.2 milliseconds after low-intensity stimulation (average 0.32 mA), with an intensity-dependent amplitude increase into the noxious range (0.4-3.2 mA). The N1 amplitude was significantly reduced by 10 mg/kg tapentadol (40.2 ± 12.5% vs vehicle 96.2 ± 8.0%) and 30 mg/kg lacosamide (46.3 ± 20.9% lacosamide vs vehicle 115 ± 5.9%) at 60 minutes after intraperitoneal administration. Tapentadol also reduced the N1 amplitude in the noxious range. Lacosamide increased the stimulus current required to evoke the half maximal N1 response (EC50), without reducing the maximum N1 amplitude in the noxious range. Pregabalin (at any dose up to 30 mg/kg) did not modulate the N1 amplitude. These results show that the spinal N1 is differentially modulated in a way that reflects distinct mechanisms of analgesic action consistent with it being a translatable biomarker of target engagement.