Brain Research, 571 (1992) 199-203 © 1992 Elsevier Science Publishers B.V. All rights reserved. 0006-8993/92/$05.00
199
BRES 17375
Streptozotocin-induced diabetes selectively alters the potency of analgesia produced by/z-opioid agonists, but not by 6- and c-opioid agonists Junzo Kamei, Yosuke Ohhashi, Taro Aoki, Naoya Kawasima and Yutaka Kasuya Department of Pharmacology, School of Pharmacy, Hoshi University, Shinagawa-ku, Tokyo (Japan) (Accepted 10 September 1991)
Key words: Diabetes; Antinociception;/~-Opioid receptor; 8-Opioid receptor; r-Opioid receptor; Mouse
To investigate the possible mechanisms of the alterations in morphine-induced analgesia observed in diabetic mice, we examined the influence of streptozotocin-induced (STZ-induced) diabetes on analgesia mediated by the different opioid receptors. The antinociceptive potency of morphine (10 mg/kg), administered s.c., as determined by both the tail-pinch and the tail-flick test, was significantly reduced in diabetic mice as compared to that in controls. Mice with STZ-induced diabetes had significantly decreased sensitivity to intracerebroventricularly (i.c.v.) administered/z-opioid agonists, such as morphine (10 ktg) and [D-AIa2,N-MePhea,Gly-olS]enkephalin (DAMGO, 0.5 ktg). However, i.c.v, administration of [D-Pen2"5]enkephalin (DPDPE, 5 ktg), a 6-opioid agonist, and U-50,488H (50/~g), a r-opioid agonist, produced pronounced antinociception in both control and diabetic mice. Furthermore, there were no significant differences in antinociceptive potency between diabetic and control mice when morphine (1 big), DAMGO (10/~g), DPDPE (0.5 ktg) or U-50,488H (50 k~g) was administered intrathecally. In conclusion, mice with STZ-induced diabetes are selectively hyporesponsive to supraspinal kt-opioid receptor-mediated antinociception, but they are normally responsive to activation of 6- and r-opioid receptors. INTRODUCTION Many studies have suggested that diabetes or hyperglycemia alters the sensitivity of laboratory animals to various pharmacological agents 5'8'12'25'26. Several studies have demonstrated that rats and mice with streptozotocin-induced (STZ-induced) diabetes and spontaneously diabetic mice are significantly less sensitive than controls to the antinociceptive effects of morphine 2°'22. In such diabetic animals, the threshold for pain perception is reduced 7'10'11. However, little information is available about the mechanism responsible for the alterations in the antinociceptive potency of morphine. Opioid analgesia has been associated with/X-, 6-, and r-opioid receptors 9'13A4'23. Both the morphine selectivity of the/x-receptor and its distribution in regions of the brain that play a putative role in the regulation of the perception of pain strongly suggest that the/x-receptor is a major factor in the supraspinal mediation of opioid analgesia 13'23. Therefore, if the reduction in the antinociceptive potency of morphine in diabetic mice is caused by the dysfunction of/x-opioid receptors, then antinociceptive potency in diabetic mice should not be reduced when such mice are treated with various agonists that
selectively activate other opioid receptors, such as 6- and r-opioid receptors. To test this hypothesis, we evaluated the antinociceptive effects of subcutaneous (s.c.), intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration of selective agonists of #-receptors ([D-AIa2,NMe Phe4,Gly-olS]enkephalin D A M G O ) , 6-receptors ([DPen2'5]enkephalin, D P D P E ) and r-receptors (U-50, 488H) in diabetic mice in a comparison with control mice.
MATERIALS AND METHODS
Subjects Male mice of the ICR strain (Tokyo Animal Laboratory Inc., Tokyo, Japan), weighing about 20 g at the beginning of the experiments, were used. They had free access to food and water in an animal room which was maintained at 22 + I°C with a 12-h lightdark cycle.
Induction of diabetes by streptozotocin Animals were rendered diabetic by an injection of streptozotocin (STZ; 200 mg/kg, i.v.) prepared in 0.1 N citrate buffer at pH 4.5. Age-matched control mice were injected with the vehicle alone. The experiments were conducted 2 weeks after injection of vehicle or STZ. Mice with serum glucose levels above 400 mg/dl were considered diabetic.
Correspondence: J. Kamei, Department of Pharmacology, School of Pharmacy, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo 142, Japan.
202 diabetic and control mice. The present results confirm that the reduction in the antinociceptive potency of morphine in diabetic mice is due to the dysfunction of supraspinal mediation of opioid analgesia. However, the antinociceptive potency of s.c. administered U-50,488H, a ~¢-opioid agonist, was not significantly reduced in diabetic mice. Furthermore, i.t. administration of U-50, 488H resulted in significant antinociception in diabetic mice which was approximately equipotent to that in control mice. In diabetic mice i.t. D P D P E , a d-opioid agonist, produces significant analgesia in a manner similar to that induced by U-50,488H. These results suggest that the function of antinociceptive mechanisms mediated by d- and r-opioid receptors, at both the supraspinal and spinal levels, may not be altered in diabetic mice. The mechanism leading to the selective hyporesponsiveness to antinociception mediated by kt-opioid agonists in diabetic mice is unclear. It is also unclear at the present time whether the defect in the response of diabetic mice to/~-opioid agonists is related to a decreased population of kt-opioid receptors or to some other defect in the overall receptor-effector sequence of events. Studies of opiate-receptor binding have shown the presence of both high- and low-affinity binding sites for [3H]naloxone and [3H]dihydromorphine in brain membranes 2'16. The administration in vivo of naloxazone was reported to inhibit selectively the binding to the high-affinity sites for these ligands and to decrease significantly the antinociceptive potency of morphine 17. Thus, it appeared that the high-affinity binding sites were primarily involved in mediating the analgesic effects of morphine. However, Brase et al. 1 reported that there were no differences in the high-affinity binding of [3H]naloxone between spontaneously diabetic (db/db) C57BL/KsJ mice and corresponding controls. Furthermore, STZ-induced diabetes also did not affect the high-affinity binding of [3H]naloxone 1. It seems likely, therefore, that the decreased potency of kt-opioid agonists in diabetic mice is
not due to an alteration in the affinity or size of the population of #-opioid receptors. In antinociceptive tests diabetic mice and mice of the beige-J strain (C57BL/6J-bgJ/bgJ) is react in a similar manner. Mathiasen et al. ~5 reported that beige-J mice are considerably less responsive than their normal littermates to the analgesic effects of centrally administered B-opioid agonists, such as morphine and D A M G O , but they are normally responsive to the O-opioid agonist [o-Pen2,L-PenS]enkephalin. The fact that the analgesic defect of beige-J mice can be reversed suggested that their insensitivity to morphine is not due to a genetic inability to synthesize functional kt-opioid receptors, but rather that the analgesic response may somehow be repressed by an endogenous substance 19. Indeed, Raffa et al. ~9 have reported that some circulating substance(s) that originate(s) in mononuclear spleen cells may contribute to the demonstrated poor analgesic response of beige-J mice to kt-opioid agonists, such as morphine and D A M G O . In this respect, it is reasonable to speculate that the abnormally low efficacy of g-opioid agonists in diabetic mice may be due to some factor derived from spleen cells, as in beige-J mice. However, it is premature to attribute the hyporesponsiveness of diabetic mice to such factors. Experiments are presently underway to determine the contribution to this phenomenon of factors from spleen cells in diabetic mice. We conclude that, although the mechanism is unclear, the diabetic mouse is selectively hyporesponsive to antinociception mediated by supraspinal ~-opioid receptors, but it is normally responsive to activation of 6- and ~c-opioid receptors.
Acknowledgements. We are grateful to the Upjohn Company for the generous gift of U-50,488H. We would also like to thank Ms. Atsuko Ishida and Ms. Takako Ohtsubo for their excellent technical assistance.
REFERENCES 1 Brase, D.A., Han, T.H. and Dewey, W.L., Effects of glucose and diabetes on binding of naloxone and dihydromorphine to opiate receptors in mouse brain, Diabetes, 36 (1987) 1173-1177. 2 Childers, S.R. and Snyder, S.H., Differential regulation by guanine nucleotides of opiate agonist and antagonist receptor interactions, J. Neurochem., 34 (1980) 583-593. 3 Cowan, A., Zhu, X.S. and Porreca, E, Studies in vivo with ICI 174864 and [D-Pen2,o-PenS]enkephalin, Neuropeptides, 5 (1985) 311-314. 4 Dewey, W.L., Harris, L.S., Howes, J.P. and Nuite, J.A., The effects of various neurohormonal modulators on the activity of morphine and the narcotic antagonists in the tail-flick and phenylquinone tests, J. Pharmacol. Exp. Ther., 175 (1970) 435440. 5 Fernando, J.C.R. and Curzon, G., Effect of D-amphetamine on
6 7
8
9
tryptophan and other aromatic amino acids in brain, Eur. J. Pharmacol., 30 (1978) 339-349. Fields, H.L., Emson, P.C., Leigh, B.K., Gilbert, R.T.F. and Iversen, L.L., Multiple opiate receptors in primary afferent fibers, Nature, 214 (1980) 351-352. Forman, L.J., Estilow, S., Lewis, M. and Vasilenko, P., Streptozotocin diabetes alters immunoreactive fl-endorphine levels and pain perception after 8 wk (s.m.) in female rats, Diabetes, 35 (1986) 1309-1313. Hanasato, G.K., Cote, M.G. and Plaa, G.L., Potentiation of carbon tetrachloride-induced hepatotoxicity in alloxan- or streptozotocin-diabetic rat, J. Pharmacol. Exp. Ther., 192 (1975) 592-604. Jaffe, J.H. and Martin, W.R., Opioid analgesics and antagonists. In A.G. Gilman, T.W. Rail, A.S. Nies and E Murad (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, MacMillan, New York, 1990, pp. 485-521.
203 10 Kamei, J., Ogawa, M. and Kasuya, Y., Development of supersensitivity to substance P in the spinal cord of the streptozotocin-induced diabetic rats, Pharmacol. Biochem. Behav., 35 (1990) 473-475. 11 Kamei, J., Ohhashi, Y., Aoki, T. and Kasuya, Y., Streptozotocin-induced diabetes in mice reduces the nociceptive threshold, as recognized after application of noxious mechanical stimuli but not of thermal stimuli, Pharmacol. Biochern. Behav., 39 (1991) 541-544. 12 Mackenzie, R.G. and Trulson, M.E., Reduced sensitivity to L-tryptophan and p-chloroamphetamine in streptozotocin-diabetic rats, J. Pharm. Pharmacol., 30 (1978) 131-132. 13 Mansour, A., Khachaturian, H., Lewis, M.E., Akil, H. and Watson, S.L., Anatomy of CNS opioid receptors, Trends Neurosci., 11 (1988) 308-316. 14 Martin, W.R., Pharmacology of opioids, Pharmacol. Rev., 35 (1984) 283-323. 15 Mathiasen, J.R., Raffa, R.B. and Vaught, J.L., C57BL/6J-bgJ (beige) mice: differential sensitivity in the tail flick test to centrally administered mu- and delta-opioid receptor agonists, Life Sci., 40 (1987) 1989-1994. 16 Pasternak, G.W. and Snyder, S.H., Identification of novel high affinity opiate receptor binding in rat brain, Nature, 253 (1975) 563-565. 17 Pasternak, G.W., Childers, S.R. and Snyder, S.H., Naloxazone, a long-acting opiate antagonist: effects on analgesia in intact animals and on opiate receptor binding in vitro, J. Pharmacol. Exp. Ther., 214 (1980) 455-462. 18 Radriguez, R.E., Leighton, G.E., Hill, R.G. and Hughes, J., In vivo evidence for spinal delta-opiate receptor operated antinociception, Neuropeptides, 8 (1986) 221-241. 19 Raffa, R.B., Kimball, E.S. and Mathiasen, J.R., The analgesic defect of C57BLI6J-bgJIbgJ (beige-J; Chediak-Higashi syndrome) mice transmitted by adoptive transfer of spleen cells to normal littermates, Life Sci., 42 (1988) 1231-1236.
20 Raz, I., Hasdai, D., Seltzer, Z. and Melmed, R.N., Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats, Diabetes, 37 (1988) 1253-1259. 21 Schmauss, C. and Yaksh, T.L., In vivo studies on spinal opiate systems mediating antinociception. II. Pharmacological profiles suggesting a differential association with mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat, J. Pharmacol. Exp. Ther., 228 (1984) 1-12. 22 Simon, G.S. and Dewey, W.L., Narcotics and diabetes. I. The effects of streptozotocin-induced diabetes on the antinociceptive potency of morphine, J. PharmacoL Exp. Ther., 218 (1981) 318-323. 23 Snyder, S.H., Drug and neurotransmitter receptors in the brain, Science, 101 (1987) 22-31. 24 Stevens, C.W. and Yaksh, T.L., Dynorphin A and related peptides administered intrathecally in the rat: a search for putative kappa opiate receptor activity, J. Pharmacol. Exp. Ther., 238 (1986) 833-838. 25 Strother, A., Trockmorton, J.K. and Herzer, C., The influence of high sugar consumption by mice on the duration of action of barbiturates and in vitro metabolism of barbiturates, aniline and p-nitroanisole, J. Pharmacol. Exp. Ther., 179 (1971) 490-498. 26 Strother, A., Effects of glucose on enzyme activity and duration of drug action, Fed. Proc., 38 (1979) 366. 27 Tiseo, P.J., Geller, E.B. and Martin, W.A., Antinociceptive action of intracerebroventrieularly administered dynorphin and other peptides in the rat, J. Pharmacol. Exp. Ther., 246 (1988) 449-453. 28 Traynor, J.R., Kelly, P.D. and Rance, M.J., Multiple opiate binding sites in the rat spinal cord, Life Sci., 31 (1982) 13771380. 29 Yaksh, T.L. and Rudy, T.A., Studies on the direct spinal action of narcotics in the production of analgesia in the rat, J. PharmacoL Exp. Ther., 202 (1977) 411-428.
199
BRES 17375
Streptozotocin-induced diabetes selectively alters the potency of analgesia produced by/z-opioid agonists, but not by 6- and c-opioid agonists Junzo Kamei, Yosuke Ohhashi, Taro Aoki, Naoya Kawasima and Yutaka Kasuya Department of Pharmacology, School of Pharmacy, Hoshi University, Shinagawa-ku, Tokyo (Japan) (Accepted 10 September 1991)
Key words: Diabetes; Antinociception;/~-Opioid receptor; 8-Opioid receptor; r-Opioid receptor; Mouse
To investigate the possible mechanisms of the alterations in morphine-induced analgesia observed in diabetic mice, we examined the influence of streptozotocin-induced (STZ-induced) diabetes on analgesia mediated by the different opioid receptors. The antinociceptive potency of morphine (10 mg/kg), administered s.c., as determined by both the tail-pinch and the tail-flick test, was significantly reduced in diabetic mice as compared to that in controls. Mice with STZ-induced diabetes had significantly decreased sensitivity to intracerebroventricularly (i.c.v.) administered/z-opioid agonists, such as morphine (10 ktg) and [D-AIa2,N-MePhea,Gly-olS]enkephalin (DAMGO, 0.5 ktg). However, i.c.v, administration of [D-Pen2"5]enkephalin (DPDPE, 5 ktg), a 6-opioid agonist, and U-50,488H (50/~g), a r-opioid agonist, produced pronounced antinociception in both control and diabetic mice. Furthermore, there were no significant differences in antinociceptive potency between diabetic and control mice when morphine (1 big), DAMGO (10/~g), DPDPE (0.5 ktg) or U-50,488H (50 k~g) was administered intrathecally. In conclusion, mice with STZ-induced diabetes are selectively hyporesponsive to supraspinal kt-opioid receptor-mediated antinociception, but they are normally responsive to activation of 6- and r-opioid receptors. INTRODUCTION Many studies have suggested that diabetes or hyperglycemia alters the sensitivity of laboratory animals to various pharmacological agents 5'8'12'25'26. Several studies have demonstrated that rats and mice with streptozotocin-induced (STZ-induced) diabetes and spontaneously diabetic mice are significantly less sensitive than controls to the antinociceptive effects of morphine 2°'22. In such diabetic animals, the threshold for pain perception is reduced 7'10'11. However, little information is available about the mechanism responsible for the alterations in the antinociceptive potency of morphine. Opioid analgesia has been associated with/X-, 6-, and r-opioid receptors 9'13A4'23. Both the morphine selectivity of the/x-receptor and its distribution in regions of the brain that play a putative role in the regulation of the perception of pain strongly suggest that the/x-receptor is a major factor in the supraspinal mediation of opioid analgesia 13'23. Therefore, if the reduction in the antinociceptive potency of morphine in diabetic mice is caused by the dysfunction of/x-opioid receptors, then antinociceptive potency in diabetic mice should not be reduced when such mice are treated with various agonists that
selectively activate other opioid receptors, such as 6- and r-opioid receptors. To test this hypothesis, we evaluated the antinociceptive effects of subcutaneous (s.c.), intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration of selective agonists of #-receptors ([D-AIa2,NMe Phe4,Gly-olS]enkephalin D A M G O ) , 6-receptors ([DPen2'5]enkephalin, D P D P E ) and r-receptors (U-50, 488H) in diabetic mice in a comparison with control mice.
MATERIALS AND METHODS
Subjects Male mice of the ICR strain (Tokyo Animal Laboratory Inc., Tokyo, Japan), weighing about 20 g at the beginning of the experiments, were used. They had free access to food and water in an animal room which was maintained at 22 + I°C with a 12-h lightdark cycle.
Induction of diabetes by streptozotocin Animals were rendered diabetic by an injection of streptozotocin (STZ; 200 mg/kg, i.v.) prepared in 0.1 N citrate buffer at pH 4.5. Age-matched control mice were injected with the vehicle alone. The experiments were conducted 2 weeks after injection of vehicle or STZ. Mice with serum glucose levels above 400 mg/dl were considered diabetic.
Correspondence: J. Kamei, Department of Pharmacology, School of Pharmacy, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo 142, Japan.
202 diabetic and control mice. The present results confirm that the reduction in the antinociceptive potency of morphine in diabetic mice is due to the dysfunction of supraspinal mediation of opioid analgesia. However, the antinociceptive potency of s.c. administered U-50,488H, a ~¢-opioid agonist, was not significantly reduced in diabetic mice. Furthermore, i.t. administration of U-50, 488H resulted in significant antinociception in diabetic mice which was approximately equipotent to that in control mice. In diabetic mice i.t. D P D P E , a d-opioid agonist, produces significant analgesia in a manner similar to that induced by U-50,488H. These results suggest that the function of antinociceptive mechanisms mediated by d- and r-opioid receptors, at both the supraspinal and spinal levels, may not be altered in diabetic mice. The mechanism leading to the selective hyporesponsiveness to antinociception mediated by kt-opioid agonists in diabetic mice is unclear. It is also unclear at the present time whether the defect in the response of diabetic mice to/~-opioid agonists is related to a decreased population of kt-opioid receptors or to some other defect in the overall receptor-effector sequence of events. Studies of opiate-receptor binding have shown the presence of both high- and low-affinity binding sites for [3H]naloxone and [3H]dihydromorphine in brain membranes 2'16. The administration in vivo of naloxazone was reported to inhibit selectively the binding to the high-affinity sites for these ligands and to decrease significantly the antinociceptive potency of morphine 17. Thus, it appeared that the high-affinity binding sites were primarily involved in mediating the analgesic effects of morphine. However, Brase et al. 1 reported that there were no differences in the high-affinity binding of [3H]naloxone between spontaneously diabetic (db/db) C57BL/KsJ mice and corresponding controls. Furthermore, STZ-induced diabetes also did not affect the high-affinity binding of [3H]naloxone 1. It seems likely, therefore, that the decreased potency of kt-opioid agonists in diabetic mice is
not due to an alteration in the affinity or size of the population of #-opioid receptors. In antinociceptive tests diabetic mice and mice of the beige-J strain (C57BL/6J-bgJ/bgJ) is react in a similar manner. Mathiasen et al. ~5 reported that beige-J mice are considerably less responsive than their normal littermates to the analgesic effects of centrally administered B-opioid agonists, such as morphine and D A M G O , but they are normally responsive to the O-opioid agonist [o-Pen2,L-PenS]enkephalin. The fact that the analgesic defect of beige-J mice can be reversed suggested that their insensitivity to morphine is not due to a genetic inability to synthesize functional kt-opioid receptors, but rather that the analgesic response may somehow be repressed by an endogenous substance 19. Indeed, Raffa et al. ~9 have reported that some circulating substance(s) that originate(s) in mononuclear spleen cells may contribute to the demonstrated poor analgesic response of beige-J mice to kt-opioid agonists, such as morphine and D A M G O . In this respect, it is reasonable to speculate that the abnormally low efficacy of g-opioid agonists in diabetic mice may be due to some factor derived from spleen cells, as in beige-J mice. However, it is premature to attribute the hyporesponsiveness of diabetic mice to such factors. Experiments are presently underway to determine the contribution to this phenomenon of factors from spleen cells in diabetic mice. We conclude that, although the mechanism is unclear, the diabetic mouse is selectively hyporesponsive to antinociception mediated by supraspinal ~-opioid receptors, but it is normally responsive to activation of 6- and ~c-opioid receptors.
Acknowledgements. We are grateful to the Upjohn Company for the generous gift of U-50,488H. We would also like to thank Ms. Atsuko Ishida and Ms. Takako Ohtsubo for their excellent technical assistance.
REFERENCES 1 Brase, D.A., Han, T.H. and Dewey, W.L., Effects of glucose and diabetes on binding of naloxone and dihydromorphine to opiate receptors in mouse brain, Diabetes, 36 (1987) 1173-1177. 2 Childers, S.R. and Snyder, S.H., Differential regulation by guanine nucleotides of opiate agonist and antagonist receptor interactions, J. Neurochem., 34 (1980) 583-593. 3 Cowan, A., Zhu, X.S. and Porreca, E, Studies in vivo with ICI 174864 and [D-Pen2,o-PenS]enkephalin, Neuropeptides, 5 (1985) 311-314. 4 Dewey, W.L., Harris, L.S., Howes, J.P. and Nuite, J.A., The effects of various neurohormonal modulators on the activity of morphine and the narcotic antagonists in the tail-flick and phenylquinone tests, J. Pharmacol. Exp. Ther., 175 (1970) 435440. 5 Fernando, J.C.R. and Curzon, G., Effect of D-amphetamine on
6 7
8
9
tryptophan and other aromatic amino acids in brain, Eur. J. Pharmacol., 30 (1978) 339-349. Fields, H.L., Emson, P.C., Leigh, B.K., Gilbert, R.T.F. and Iversen, L.L., Multiple opiate receptors in primary afferent fibers, Nature, 214 (1980) 351-352. Forman, L.J., Estilow, S., Lewis, M. and Vasilenko, P., Streptozotocin diabetes alters immunoreactive fl-endorphine levels and pain perception after 8 wk (s.m.) in female rats, Diabetes, 35 (1986) 1309-1313. Hanasato, G.K., Cote, M.G. and Plaa, G.L., Potentiation of carbon tetrachloride-induced hepatotoxicity in alloxan- or streptozotocin-diabetic rat, J. Pharmacol. Exp. Ther., 192 (1975) 592-604. Jaffe, J.H. and Martin, W.R., Opioid analgesics and antagonists. In A.G. Gilman, T.W. Rail, A.S. Nies and E Murad (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, MacMillan, New York, 1990, pp. 485-521.
203 10 Kamei, J., Ogawa, M. and Kasuya, Y., Development of supersensitivity to substance P in the spinal cord of the streptozotocin-induced diabetic rats, Pharmacol. Biochem. Behav., 35 (1990) 473-475. 11 Kamei, J., Ohhashi, Y., Aoki, T. and Kasuya, Y., Streptozotocin-induced diabetes in mice reduces the nociceptive threshold, as recognized after application of noxious mechanical stimuli but not of thermal stimuli, Pharmacol. Biochern. Behav., 39 (1991) 541-544. 12 Mackenzie, R.G. and Trulson, M.E., Reduced sensitivity to L-tryptophan and p-chloroamphetamine in streptozotocin-diabetic rats, J. Pharm. Pharmacol., 30 (1978) 131-132. 13 Mansour, A., Khachaturian, H., Lewis, M.E., Akil, H. and Watson, S.L., Anatomy of CNS opioid receptors, Trends Neurosci., 11 (1988) 308-316. 14 Martin, W.R., Pharmacology of opioids, Pharmacol. Rev., 35 (1984) 283-323. 15 Mathiasen, J.R., Raffa, R.B. and Vaught, J.L., C57BL/6J-bgJ (beige) mice: differential sensitivity in the tail flick test to centrally administered mu- and delta-opioid receptor agonists, Life Sci., 40 (1987) 1989-1994. 16 Pasternak, G.W. and Snyder, S.H., Identification of novel high affinity opiate receptor binding in rat brain, Nature, 253 (1975) 563-565. 17 Pasternak, G.W., Childers, S.R. and Snyder, S.H., Naloxazone, a long-acting opiate antagonist: effects on analgesia in intact animals and on opiate receptor binding in vitro, J. Pharmacol. Exp. Ther., 214 (1980) 455-462. 18 Radriguez, R.E., Leighton, G.E., Hill, R.G. and Hughes, J., In vivo evidence for spinal delta-opiate receptor operated antinociception, Neuropeptides, 8 (1986) 221-241. 19 Raffa, R.B., Kimball, E.S. and Mathiasen, J.R., The analgesic defect of C57BLI6J-bgJIbgJ (beige-J; Chediak-Higashi syndrome) mice transmitted by adoptive transfer of spleen cells to normal littermates, Life Sci., 42 (1988) 1231-1236.
20 Raz, I., Hasdai, D., Seltzer, Z. and Melmed, R.N., Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats, Diabetes, 37 (1988) 1253-1259. 21 Schmauss, C. and Yaksh, T.L., In vivo studies on spinal opiate systems mediating antinociception. II. Pharmacological profiles suggesting a differential association with mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat, J. Pharmacol. Exp. Ther., 228 (1984) 1-12. 22 Simon, G.S. and Dewey, W.L., Narcotics and diabetes. I. The effects of streptozotocin-induced diabetes on the antinociceptive potency of morphine, J. PharmacoL Exp. Ther., 218 (1981) 318-323. 23 Snyder, S.H., Drug and neurotransmitter receptors in the brain, Science, 101 (1987) 22-31. 24 Stevens, C.W. and Yaksh, T.L., Dynorphin A and related peptides administered intrathecally in the rat: a search for putative kappa opiate receptor activity, J. Pharmacol. Exp. Ther., 238 (1986) 833-838. 25 Strother, A., Trockmorton, J.K. and Herzer, C., The influence of high sugar consumption by mice on the duration of action of barbiturates and in vitro metabolism of barbiturates, aniline and p-nitroanisole, J. Pharmacol. Exp. Ther., 179 (1971) 490-498. 26 Strother, A., Effects of glucose on enzyme activity and duration of drug action, Fed. Proc., 38 (1979) 366. 27 Tiseo, P.J., Geller, E.B. and Martin, W.A., Antinociceptive action of intracerebroventrieularly administered dynorphin and other peptides in the rat, J. Pharmacol. Exp. Ther., 246 (1988) 449-453. 28 Traynor, J.R., Kelly, P.D. and Rance, M.J., Multiple opiate binding sites in the rat spinal cord, Life Sci., 31 (1982) 13771380. 29 Yaksh, T.L. and Rudy, T.A., Studies on the direct spinal action of narcotics in the production of analgesia in the rat, J. PharmacoL Exp. Ther., 202 (1977) 411-428.
