Pontospinal noradrenergic neurons form part of the endogenous analgesic system. Plastic changes in this system are thought to be involved in the development of neuropathic pain although previous subtractive approaches to block descending noradrenergic control have been inconclusive (e.g. Howorth et al 2009). Here we use a sequential, repeated catecholaminergic antagonist approach to investigate whether the descending noradrenergic system has a protective role against the development of neuropathic pain using a chronic intrathecal catheter system. Neuropathy was induced in male Wistar rats (300-350g, n=11) using a variation of the spared nerve injury (SNIt) model (tibial nerve ligation and transection (Lee et al., 2000)) under ketamine (50mg/kg) and medetomidine (300µg/kg) anaesthesia i.p. At the same time a chronic intrathecal catheter was implanted at the L5/L6 interspace. Behavioural responses to mechanical (von Frey), cold (acetone) and heat (Hargreaves’) stimulation were assayed at baseline and at days 3, 5, 10, 12, 17 and 19 post-surgery. The influence of the descending noradrenergic control over time was tested after single intrathecal dosing with either yohimbine (α2 antagonist, 30µg) or prazosin (α1 antagonist, 30µg). Values are expressed as mean ± SEM, compared by two-way ANOVA. Tibial nerve injury resulted in the development of robust neuropathic signs in the ipsilateral hindlimb by day 10. However, spinal yohimbine unmasked allodynia and hyperalgesia at an earlier stage (e.g. day 3 mechanical threshold: 14.8 ± 2.5g Vs + yohimbine 5.7 ± 1.3g P<0.01 n=6). The SNIt animals showed normal sensation in the contralateral limb, however the same animals treated with yohimbine showed robust cold allodynia from day 3 (day 3: 8 ± 4% paw withdrawal frequency Vs + yohimbine: 64 ± 8% paw withdrawal frequency, P<0.001 n=5) and heat hyperalgesia (day 3: Hargreaves paw withdrawal latency: 13.9 ± 1.0s Vs + yohimbine: 10.4 ± 0.8s P<0.05 n=5). Similarly, yohimbine unmasked robust contralateral mechanical allodynia by day 17 (day 17: 13.9 ± 2.2g Vs + yohimbine: 3.5 ± 1.1g P<0.01 n=6). Yohimbine was without effect in sham animals (n=3). Spinal prazosin did not have an effect at any time point. Thus, endogenous tone in descending noradrenergic systems completely masks the development of contralateral and delays the development of ipsilateral sensitization. Contralateral pain in animal models and in the clinic may therefore be due to a lack of, or reduced activation of these inhibitory systems providing a rationale for the use of noradrenaline re-uptake inhibitors in treating bilateral neuropathic pain. It remains to be determined why the noradrenergic system fails to completely suppress the sensitization of the ipsilateral limb.