Antinociceptive Effect of Morphine, but not μ Opioid Receptor Number, Is Attenuated in the Spinal Cord of Diabetic Rats

Background: The mechanisms of decreased analgesic potency of μ opioids in diabetic neuropathic pain are not fully known. The authors recently found that G protein activation stimulated by the μ opioid agonist is significantly reduced in the spinal cord dorsal horn in diabetes. In the current study, they determined potential changes in the number and binding affinity of μ opioid receptors in the spinal cord in diabetic rats. Methods: Rats were rendered diabetic with an intraperitoneal injection of streptozotocin. The nociceptive withdrawal threshold was measured before and after intrathecal injection of morphine by applying a noxious pressure stimulus to the hind paw. The μ opioid receptor was determined with immunocytochemistry labeling and a specific μ opioid receptor radioligand, [³H]-(D-Ala², N-Me-Phe⁴, Gly-ol⁵)-enkephalin ([³H]-DAMGO), in the dorsal spinal cord obtained from age-matched normal and diabetic rats 4 weeks after streptozotocin treatment. Results: The antinociceptive effect of intrathecal morphine (2-10 μg) was significantly reduced in diabetic rats, with an ED₅₀ about twofold higher than that in normal rats. However, both the dissociation constant (3.99 ± 0.22 vs. 4.01 ± 0.23 nM) and the maximal specific binding (352.78 ± 37.26 vs. 346.88 ± 35.23 fmol/mg protein) of [³H]-DAMGO spinal membrane bindings were not significantly different between normal and diabetic rats. The μ opioid receptor immunoreactivity in the spinal cord dorsal horn also was similar in normal and diabetic rats. Conclusions: The reduced analgesic effect of intrathecal morphine in diabetes is probably due to impairment of μ opioid receptor-G protein coupling rather than reduction in μ opioid receptor number in the spinal cord dorsal horn.