Free fatty acid 1 (FFA1) receptor modulation in experimental arthritis in male and female mice subjected to environmental enrichment.

BACKGROUND AND PURPOSE: Few animal studies examine sex dimorphism and environmental enrichment (EE) when evaluating pharmacological strategies for inflammatory pain. We explored the interaction between environmental enrichment, sex and FFA1 receptor modulation in a mouse model of inflammatory pain.

EXPERIMENTAL APPROACH: C57BL/6J mice received complete Freund's adjuvant (CFA) intraplantarly and were assessed for pain and inflammation over 21 days. They received the FFA1 partial agonist GW9508 (2 and 8 mg·kg-1) or the selective antagonist GW1100 (4 mg·kg-1) from days 7 to 14 under standard or environmental enrichment conditions. Paw leukocyte migration was evaluated histologically, and cortical expression of brain-derived neurotrophic factor (BDNF) and FFA1 receptors was assessed by immunohistochemistry.

KEY

RESULTS

GW9508 reduced mechanical sensitivity in males and females at 8 and 2 mg·kg-1, respectively. Thermal sensitivity showed greater improvement at the lower dose, with synergistic effects under environmental enrichment. Only females responded to FFA1 receptor modulation in oedema assessments. GW9508 reduced paw leukocyte migration in females, particularly under EE, whereas males showed no environmental differences. GW9508 increased cortical BDNF counts in both females (2 mg·kg-1) and males (8 mg·kg-1). Cortical FFA1 receptor expression decreased in GW1100 groups, irrespective of environmental enrichment. Conversely, males showed an increased FFA1 receptor immunopositivity under GW9508 treatment (8 mg·kg-1) combined with environmental enrichment. BDNF and FFA1 receptor immunopositivity in the anterior cingulate cortex (ACC) was higher with GW9508 (8 mg·kg-1) for both sexes.

CONCLUSION AND IMPLICATIONS: These findings highlight the interaction between environmental enrichment and FFA1 receptors, emphasizing sex differences in responses to chronic inflammatory pain.