We studied whether striatal α2-adrenoceptors or N-methyl-d-aspartate (NMDA) receptors influence descending regulation of neuropathic hypersensitivity in the rat by microinjecting an α2-adrenoceptor agonist or NMDA-receptor antagonist into the dorsal striatum in animals with a spinal nerve ligation-induced neuropathy. Hypersensitivity was assessed in the hind limb by monofilaments and paw pressure test. Various neurotransmitter receptor antagonists were administered into the striatum or intrathecally to determine striatal and spinal neurotransmitters mediating the modulatory influence. The results indicate that the striatum has a dual effect on neuropathic hypersensitivity via two distinct pathways descending to the spinal cord. First, hypersensitivity is reduced following activation of noradrenergic α2-adrenoceptors and downstream dopamine D2 receptors in the striatum. This antihypersensitivity effect is predominantly ipsilateral and it descends via parallel dopaminergic and serotoninergic pathways to act on spinal dopamine D2 and 5-HT1A receptors, respectively. Second, tonic activation of striatal NMDA receptors promotes hypersensitivity by suppressing spinal GABAergic inhibition. The antihypersensitivity actions induced by striatal drug administrations were not associated with motor effects as suggested by lack of effect on the threshold of the uninjured limb or amplitude of the innocuous H-reflex. Involvement of striatal dopamine D2 receptors in the noradrenergic pain inhibitory circuitry may explain why disorders causing hypofunction of the striatal dopaminergic system, such as in Parkinson’s disease, have been associated with pain. Furthermore, our findings indicate that striatal NMDA receptors provide a tonic supramedullary drive for medullospinal facilitatory influence that is known to be of importance for neuropathic hypersensitivity.