Sex-specific differences in nociceptive behaviour and the amygdala endocannabinoid system in the rat monoiodoacetate-induced knee osteoarthritis model

Abstract

Introduction

Osteoarthritis (OA) is a chronic, progressive joint disorder with higher prevalence and pain severity in women than men. The endocannabinoid system (ECS) modulates pain and shows sexual dimorphism, yet sex-specific alterations in central ECS signalling in OA pain remain under-investigated.

Objectives

We investigated sex-dependent differences in pain-related behaviours and central ECS signalling in the rat monoiodoacetate (MIA) model of knee OA pain.

Methods

Adult male and female Sprague-Dawley rats (8-9 weeks old) received an intra-articular injection of either MIA (2 mg/50 μL) or saline (Sham control) in the left knee. Pain-related behaviours were assessed over 63 days post-injection. The influence of oestrous cycle stage on pain-related behaviours was examined in 100 additional MIA-injected female rats. Endocannabinoids [anandamide (AEA), 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines [palmitoylethanolamide (PEA), oleoylethanolamide (OEA)] were quantified in brain and spinal cord regions (LC-MS/MS), and ECS-related gene expression (Faah, Mgll, Cnr1, Cnr2) was assessed (RT-qPCR).

Results

MIA females exhibited greater weight-bearing deficits and hind paw mechanical hypersensitivity than males throughout the study period. Oestrous cycle stage did not influence MIA-induced pain-related behaviours. MIA males showed lateralised ECS signalling in the amygdala, with elevated endocannabinoid and N-acylethanolamine levels in the ipsilateral/left amygdala, a pattern absent in females. A bilateral reduction of Mgll expression in the amygdala was observed in MIA female rats compared to Sham controls.

Conclusions

In the MIA model, female rats demonstrate greater nociceptive behaviour and a different amygdala ECS profile, compared with males, paving the way for further investigation of ECS-mediated mechanisms underlying sex differences in OA pain.