The purpose of the current study was to determine if exercise-induced muscle pain is modulated by central neural mechanisms (i.e. higher brain systems). Ratings of muscle pain perception (MPP) and perceived exertion (RPE), muscle sympathetic nerve activity (MSNA), arterial pressure, and heart rate were measured during fatiguing isometric handgrip (IHG) at 30% maximum voluntary contraction and postexercise muscle ischaemia (PEMI). The exercise trial was performed twice, before and after administration of naloxone (16 mg intravenous; n= 9) and codeine (60 mg oral; n= 7). All measured variables increased with exercise duration. During the control trial in all subjects (n= 16), MPP significantly increased during PEMI above ratings reported during IHG (6.6 ± 0.8 to 9.5 ± 1.0; P < 0.01). However, MSNA did not significantly change compared with IHG (7 ± 1 to 7 ± 1 bursts (15 s)−1), whereas mean arterial blood pressure was slightly reduced (104 ± 4 to 100 ± 3 mmHg; P < 0.05) and heart rate returned to baseline values during PEMI (83 ± 3 to 67 ± 2 beats min−1; P < 0.01). These responses were not significantly altered by the administration of naloxone or codeine. There was no significant relation between arterial blood pressure and MSNA with MPP during either IHG or PEMI. A second study (n= 8) compared MPP during ischaemic IHG to MPP during PEMI. MPP was greater during PEMI as compared with ischaemic IHG. These findings suggest that central command modulates the perception of muscle pain during exercise. Furthermore, endogenous opioids, arterial blood pressure and MSNA do not appear to modulate acute exercise-induced muscle pain.