Effect of Hyperglycemia on Pain Perception and on Efficacy of Morphine Analgesia in Rats ITMAR RAZ, DAVID HASDAI, ZEEV SELTZER, AND RAPHAEL N. MELMED The effect exerted by different hyperglycemic states on the pain threshold and on the analgesic potential of morphine was studied in male Sabra rats with the hot plate device. Hyperglycemia induced by an intraperitoneal injection of 0.014 mol/kg glucose or an acute or chronic diabetic state induced by streptozocin injection did not significantly alter the pain threshold. However, states of acute and chronic diabetes markedly blunted the analgesic effect of morphine (5 mg/kg). Sabra rats maintained on a cocktail of glucose-saccharin, thought to activate the release of endogenous opioids, demonstrated an increased pain threshold and rapidly developed resistance to the analgesic effect of morphine. Previous studies have shown that glucose in high concentration may interfere with the interaction of morphine on the opiate receptor. The influence of the diabetic state on (5- endorphin synthesis and concentration in the central nervous system is another factor that might change pain perception in diabetes. We propose that in diabetes, generally, the pain threshold is adequately maintained, despite the antagonistic effect of glucose, partly due to a compensatory increased secretion of endogenous opioid peptides. We hypothesize that in patients with chronic painful diabetic neuropathy, these normal analgesic response mechanisms may be overwhelmed either by an excess of nociceptive impulses from diseased peripheral nerves or conceivably by a failure of endogenous opioid secretory response to the hyperglycemia. Diabetes 37:1253-59, 1988 P ain is a common manifestation of diabetic neurop- athy (1); however, the etiology of the neuropathic pain is still not determined. Diabetic neuropathic pain may originate from regenerating axon sprouts (2,3). However, diabetic subjects with such neural changes may not experience neuropathic pain (4). Metabolic factors may also contribute to the development or amelioration of diabetic neuropathic pain (5,6); stringent regulation of blood glucose levels in diabetic subjects resulted in the amelio- ration of the painful symptoms (5). Thus, painful diabetic neuropathy may be the result of an interplay between pe- ripheral neuropathy and the metabolic changes in the central nervous system caused by the diabetic state. Simon and associates (7,8) demonstrated a decrease in sensitivity to morphine in streptozocin-induced diabetic (STZ-D) rats. They postulated that glucose might interfere with morphine action on the opiate receptor. Shook and Dewey (9) reported a diminished development of physical dependence on morphine in diabetic animals. They also demonstrated that high glucose concentrations in vitro have decreased the potency of normorphine in the electrically stimulated guinea pig ileum and mouse vas deferens (10), thus supporting the hypothesis that glucose might interfere with morphine action on the opiate receptor. Experimental evidence relating to the effect of diabetes on pain perception is contradictory. Chu et al. (11) reported a higher level of pain threshold in STZ-D male rats via the hot plate device. Likewise, Levine et al. (12) demonstrated prolonged tail-flick latencies to radiant heat in diabetic mice. On the other hand, Forman et al. (13) recently reported a significant reduction in the pain threshold of STZ-D female rats with the hot plate device. Morley et al. (14) demonstrated a lowered pain threshold in humans rendered acutely hy- perglycemic by glucose injection but could not demonstrate a significant change in pain threshold of diabetic patients. Diabetic rats display various changes of (3-endorphin lev- els in different regions of the brain (13,15). The significance of these changes is not clear, although, considering the im- portance of opiates in pain control (16), these changes may be important in influencing pain perception. From the Department of Medicine B and the Department of Physiology, He- brew University Hadassah Medical School, Jerusalem, Israel. Address correspondence and reprint requests to Dr. I. Raz, Department of Medicine B, Hadassah University Hospital, P.O. Box 12000, Jerusalem 91120, Israel. Received for publication 23 April 1987 and accepted in revised form 26 February 1988. DIABETES, VOL. 37, SEPTEMBER 1988 1253