Sensorimotor Alterations Induced by Novel Fentanyl Analogs in Mice: Possible Impact on Human Driving Performances

**Background:** Driving under the influence of drugs (DUID) is a growing public health concern, with novel psychoactive substances (NPS) increasingly implicated. Novel synthetic opioids (NSO), including fentanyl derivatives such as acrylfentanyl (ACRYLF), ocfentanyl (OCF), and furanylfentanyl (FUF), are a rapidly expanding class of NPS. While fentanyl is known to impair cognitive and psychomotor functions critical for driving, the effects of these newer analogs on sensorimotor performance relevant to driving are poorly understood. This study combines a literature review of human psychomotor effects with experimental data from a mouse model to evaluate the sensorimotor alterations induced by these compounds.

**Methods:** The study used male ICR (CD-1) mice (30-35 g) to assess the effects of acute intraperitoneal administration of fentanyl (FENT), ACRYLF, OCF, and FUF (0.01-15 mg/kg) on sensorimotor functions. A battery of behavioral tests evaluated visual responses (visual object response and visual placing response), acoustic responses (reflex to four different sound stimuli), and tactile responses (vibrissae, pinna, and corneal reflexes). The opioid receptor antagonist naloxone (NLX, 6 mg/kg) was administered 15 minutes before agonist injection to assess receptor involvement. Data were analyzed using two-way ANOVA followed by Bonferroni's test.

**Key Results:** All four opioids dose-dependently impaired sensorimotor functions. For visual object response, the rank order of potency (ED50) was OCF (1.60 mg/kg) ≥ ACRYLF (1.97 mg/kg) ≥ FUF (2.17 mg/kg) = FENT (2.7 mg/kg). For visual placing response, the order was OCF (0.88 mg/kg) > ACRYLF (1.38 mg/kg) ≥ FENT (1.87 mg/kg) > FUF (2.51 mg/kg). Acoustic responses were significantly impaired by OCF and FUF (ED50: FUF 2.40 mg/kg, OCF 4.36 mg/kg), while FENT and ACRYLF only affected the highest dose transiently. Tactile responses were also dose-dependently reduced, with OCF (ED50=5.85 mg/kg) more potent than FUF (ED50=9.20 mg/kg). NLX pre-treatment partially or fully blocked these effects, with a second dose often required for complete reversal, particularly for tactile responses.

**Clinical Implications:** The sensorimotor impairments observed in mice—affecting visual, acoustic, and tactile processing—parallel human findings where fentanyl impairs eye-hand coordination, reaction time, and sustained attention. The visual placing test in mice integrates vision, coordination, and proprioception, analogous to human driving tasks like braking reaction time and trail-making tests. The acoustic and tactile deficits suggest that these opioids could impair a driver's ability to process auditory cues (e.g., sirens) and maintain proprioceptive awareness. The need for repeated naloxone dosing to reverse effects in mice mirrors clinical recommendations for fentanyl overdose. Given the high similarity between mouse and human mu-opioid receptors, these findings strongly suggest that ACRYLF, OCF, and FUF pose significant risks for driving impairment, even at low doses, and underscore the importance of including these NSO in DUID toxicology screening.