Analgesic Effect of a Thromboxane A2 Receptor Agonist on Multiple Pain Models in Mice

Thromboxane A2 (TXA2), a metabolite of arachidonic acid, is well known for its role in vasoconstriction and platelet aggregation via activation of thromboxane prostanoid receptors (TPR). Although other prostanoid receptors have established roles in pain modulation, the contribution of TXA2-TPR signaling to nociceptive processing remains unclear. This study evaluated the analgesic effects of a TPR agonist in mouse models of pain.

Four-week-old male ddY mice, an outbred mouse strain, received intrathecal (i.t.) administration of (Z)-7-((1S,2R,3R,4R)-3-((R,E)-3-hydroxy-4-(4-iodophenoxy)but-1-en-1-yl)-7-oxabicyclo[2.2.1]heptan-2-yl)hept-5-enoic acid (I-BOP), a TPR agonist, in four pain models (n = 6-10 per group): hot plate test, formalin test, prostaglandin E2 (PGE2)-induced allodynia, and L5 spinal nerve transection (L5-SNT). Behavioral tests evaluated pain responses as the primary outcome. The mRNA expression levels of cyclooxygenase (COX)-1, COX-2, TXA2 synthase (TXAS), and TPR were analyzed by reverse transcription-polymerase chain reaction and compared between ipsilateral and contralateral L4-L6 spinal dorsal horns. TPR localization in the spinal dorsal horn was determined by immunohistochemistry. Data were analyzed using appropriate parametric or nonparametric tests based on the results of normality assessment. Comparisons between groups were performed using Student t test, the Mann-Whitney U test, 1-way analysis of variance (ANOVA) with Dunnett post hoc test, 2-way ANOVA with Bonferroni post hoc test, or Friedman test followed by Wilcoxon signed-rank tests with Bonferroni correction as appropriate. All behavioral assessments were conducted in a blinded manner.

In the PGE2-induced allodynia model, coadministration of I-BOP dose dependently reduced the allodynia score compared with PGE2 alone. When the response to PGE2 alone was defined as 100%, the allodynia scores were reduced to 20% (95% confidence interval [CI], -7 to 47; P = .0012) at 1 ng and 10% (95% CI, -11 to 31; P < .001) at 10 ng I-BOP. In the L5-SNT neuropathic pain model, i.t. I-BOP produced a dose-dependent elevation of mechanical withdrawal thresholds, with significant main effects of dose (P < .001) and time (P < .001) and a significant dose × time interaction (P = .0012). In the formalin test, I-BOP selectively reduced nociceptive behavior during the second phase (I-BOP 140 ± 6.2 seconds; saline 623 ± 18.1 seconds, expressed as mean ± standard error of the mean [SEM]; P = .008), without affecting the first phase. The ipsilateral spinal dorsal horn of L5-SNT mice showed increased TPR mRNA expression. Immunohistochemistry revealed TPR localization in both the substantia gelatinosa and deep laminae of the spinal dorsal horn.

These findings suggest that a TPR agonist exerts analgesic effects by acting on TPR expressed in the spinal cord, highlighting the potential role of TPR signaling in pain modulation.