Dopamine D1 and D3 receptor modulators restore morphine analgesia and prevent opioid preference in a model of neuropathic pain.

A secondary consequence of spinal cord injury (SCI) is debilitating chronic neuropathic pain, which is commonly morphine resistant and inadequately managed by current treatment options. Consequently, new pain management therapies are desperately needed. We previously reported that dopamine D3 receptor (D3R) dysfunction was associated with opioid resistance and increases in D1 receptor (D1R) protein expression in the spinal cord. Here, we demonstrate that in a model of SCI neuropathic pain, adjuvant therapy with a D3R agonist (pramipexole) or D1R antagonist (SCH 39166) can restore the analgesic effects of morphine and reduce reward potential. Prior to surgery thermal and mechanical thresholds were tested in three groups of female rats (naïve, sham, SCI). After surgery, testing was repeated under the following drug conditions: 1) saline, 2) morphine, 3) pramipexole, 4) SCH 39166, 5) morphine + pramipexole, and 6) morphine + SCH 39166. Reward potential of morphine and both combinations was assessed using conditioned place preference. Following SCI, morphine + pramipexole and morphine + SCH 39166 significantly increased both thermal and mechanical thresholds. Morphine alone induced conditioned place preference, but when combined with either the D3R agonist or D1R antagonist preference was not induced. The data suggest that adjunct therapy with receptor-specific dopamine modulators can restore morphine analgesia and decrease reward potential and thus, represents a new target for pain management therapy after SCI.

The role of the Rx homeobox gene in retinal progenitor proliferation and cell fate specification.

The Retinal homeobox gene (Rx; also Rax) plays a crucial role in the early development of the vertebrate eye. Germline deletion of Rx in mice results in the failure of optic vesicle formation, leading to anophthalmia. Recent research using conditional mouse knockout models provides some clues to the role of Rx in eye development following optic vesicle formation. However, the functions of Rx in embryonic retinogenesis are still not fully understood. We investigated the function of Rx in the mouse neural retina using a conditional knockout where the Pax6α-Cre driver deletes Rx activity in early retinal progenitors. The deletion of Rx activity causes a loss of retinal lamination, a depletion of retinal progenitors, and a change in retinal cell fate in our conditional knockout model. The deletion of Rx leads to an absence of late-born retinal neurons (rods and bipolar cells) and Müller glia at postnatal ages, as well as a loss of the early-born cone photoreceptors. Decreased BrdU labeling in the Rx-deleted portion of the retina suggests a loss of retinal progenitors via early cell cycle exit, which likely prevents the formation of late-born cells. As early-born cells, cone photoreceptors should not be as affected by early cell cycle exit of retinal progenitors. However, embryonic cone photoreceptor labeling is also markedly reduced in Rx-deleted retinas. Together these data demonstrate the importance of Rx for retinal progenitor proliferation and a specific requirement of Rx for cone formation in mice.