Non-Psychoactive Cannabinoid Modulation of Nociception and Inflammation Associated with a Rat Model of Pulpitis

Abstract

Despite advancements in dental pain management, one of the most common reasons for emergency dental care is orofacial pain. Our study aimed to determine the effects of non-psychoactive Cannabis constituents in the treatment of dental pain and related inflammation. We tested the therapeutic potential of two non-psychoactive Cannabis constituents, cannabidiol (CBD) and β-caryophyllene (β-CP), in a rodent model of orofacial pain associated with pulp exposure. Sham or left mandibular molar pulp exposures were performed on Sprague Dawley rats treated with either vehicle, the phytocannabinoid CBD (5 mg/kg i.p.) or the sesquiterpene β-CP (30 mg/kg i.p.) administered 1 h pre-exposure and on days 1, 3, 7, and 10 post-exposure. Orofacial mechanical allodynia was evaluated at baseline and post-pulp exposure. Trigeminal ganglia were harvested for histological evaluation at day 15. Pulp exposure was associated with significant orofacial sensitivity and neuroinflammation in the ipsilateral orofacial region and trigeminal ganglion. β-CP but not CBD produced a significant reduction in orofacial sensitivity. β-CP also significantly reduced the expression of the inflammatory markers AIF and CCL2, while CBD only decreased AIF expression. These data represent the first preclinical evidence that non-psychoactive cannabinoid-based pharmacotherapy may provide a therapeutic benefit for the treatment of orofacial pain associated with pulp exposure.

Keywords: cannabinoids; dental pain; pulpitis.

Figure 1

Exposure of the tooth pulp in the left mandibular molar of rats produces ipsilateral orofacial allodynia for up to 2 weeks. Effect of sham procedure or pulp exposure on mechanical withdrawal threshold on the ipsilateral side (A,C) or contralateral side (B,D). Orofacial sensitivity was measured with Von Frey filaments prior to pulp exposure procedure and again 1, 7, and 14 days post-exposure. N = 10/group. Ipsilateral and contralateral data are collected from the same rats. * p < 0.05 compared with baseline.

Figure 2

Repeated administration of β-CP significantly attenuated orofacial sensitivity in pulp-exposed rats. Effect of repeated administration (1 h prior to pulp exposure, 24 h post-exposure, and on days 3, 7, and 10 post-exposure) of CBD (5.0 mg/kg) or β-CP (30.0 mg/kg) on mechanical withdrawal threshold on the ipsilateral side (A) or contralateral side (B). β-CP significantly attenuated orofacial mechanical allodynia on the ipsilateral drilled molar side (* p < 0.05 compared with sham, # p < 0.05 compared with drilled + vehicle, N = 10/group).

Figure 3

Treatment with Cannabis constituents attenuates increases in AIF and CCL2 gene expression in the ipsilateral trigeminal ganglia following pulp exposure in rats. Gene expression was measured using RT-PCR on day 15 post pulp exposure or sham procedure. Only AIF and CCL2 were significantly upregulated. Repeated treatment with β-CP significantly attenuated expression of AIF and CCL2, while CBD only attenuated expression of AIF. * p < 0.05 compared with sham, # p < 0.05 compared with drilled + vehicle.

Figure 4

Pulp exposure is associated with a significant decrease in AIF, CCL2, and CXCL9 gene expression in the contralateral trigeminal ganglia in rats. Gene expression was measured using RT-PCR on day 15 post pulp exposure or sham procedure. * p < 0.05.