Behavioral Depression Induced by Dental Pain in Mice and its Resistance to Analgesics.

Acute dental pain contributes to ~10% of opioid analgesic prescriptions in the U.S., highlighting a critical need for safer, non-opioid alternatives. This study supports the NIH HEAL initiative by developing a preclinical model to investigate behavioral depression as one class of behavioral signs that are both caused by dental pain and useful for analgesic discovery. Specifically, we assessed depression of locomotor and oral activity and stimulation of postural hunching and facial grimace as pain-related behaviors produced by a set of dental-pain manipulations. We then evaluated effectiveness of the nonsteroidal anti-inflammatory drug ketoprofen and opioid agonist morphine to alleviate these behavioral effects. Male and female ICR mice received one of four dental-pain manipulations: (1) Control - anesthesia only, (2) Open -pulp exposure, (3) Closed-Sal - pulp exposure with saline-soaked point and sealing, (4) Closed-CFA - pulp exposure with complete Freund's adjuvant-soaked point and sealing. Locomotor activity along with posture and grimace scores were assessed 6h after surgery. Retrieval and consumption of sunflower seeds were assessed after 24h to assess oral activity required to crush the hull and extract the kernel. Relative to control treatment, dental-pain manipulations produced significant, graded depression of locomotion and seed retrieval/consumption (Open<Closed-Sal<Closed-CFA) while increasing posture and grimace scores. Ketoprofen and morphine partially improved posture but did not alleviate behavioral depression or grimace. This model demonstrates translational relevance by capturing multiple dimensions of dental-pain models in mice. The limited efficacy of ketoprofen and morphine underscore the need for novel non-opioid analgesics capable of addressing the complex behavioral consequences of dental pain. PERSPECTIVE: This article describes the impact of a set of dental-pain manipulations on endpoints of translationally relevant and pain-related behavioral depression in mice. The procedure described here could be used as a preclinical platform for use in discovery of novel analgesics for treatment of dental pain.