Introduction: Nociceptive information from the heart is transmitted via sympathetic and vagal cardiac afferents and the involvement of these pathways in the development of cardiac pain is incompletely understood. This dual innervation of the heart and other thoracic viscera, and their convergence in central integrating centres, make it challenging to decipher the mechanisms of cardiac pain, which is exacerbated by the practical issues of accessing the heart, especially in unanaesthetised animals. Given the potential benefit of investigating nociception in transgenic mouse lines, there is a surprising lack of mouse models of cardiac pain. We have extended the established working heart-brainstem preparation (WHBP; Paton 1996), a decerebrate, arterially-perfused in situ mouse model, to investigate cardiac nociception. Methods: Adult mice were anaesthetised with 5% halothane (until decerebration) for surgical set up of the WHBP. The descending aorta was cannulated with a double lumen catheter and retrogradely perfused with carbogenated (5% CO2, 95% O2) Ringer’s. Cardiac nociceptors were activated by bolus perfusion of capsaicin (1-100μM) over the epicardial surface of the heart. Simultaneous recordings were made of perfusion pressure, heart rate, phrenic nerve activity and somatic EMG of inter-scapular muscles. Data are expressed as mean±SEM or median [quartile ranges]. Results: Application of capsaicin to the epicardial surface of the heart elicited rapid, reproducible responses in cardiorespiratory, somatic and vasomotor outflows. Capsaicin produced a tachycardia (10.2 [4.9 – 22.9] bpm, n=9) and attenuated respiratory sinus arrhythmia (n=8). This was usually accompanied by a small pressor response (1.8±0.2 mmHg, n=4) consistent with sympatho-activation. Capsaicin also caused immediate bursts of somatic EMG activation (n=4). The respiratory changes were consistent within a preparation but varied across animals and consisted of tachypnoea (187%±13% of control, n=4), transient apnoea followed by tachypnoea (n=3) or a transient apnoea alone (3.4±0.9s, n=2). Interestingly, vagotomy prevented the tachycardia and also abolished the pressor and respiratory components of the responses to capsaicin (n=2). Conclusions: Epicardial application of capsaicin elicited characteristic patterns of cardiorespiratory and vasomotor changes that suggest sympathetic activation and vagal withdrawal. Our preliminary data suggest that cardiac vagal afferent transmission plays an important role in generating this co-ordinated response. This novel mouse model of cardiac pain also offers the opportunity to study genetically modified strains in combination with recordings of cardiac vagal or sympathetic nerves to determine mechanisms.