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Impaired noradrenaline homeostasis in rats with painful diabetic neuropathy as a target of duloxetine analgesia.

Kinoshita J, Takahashi Y, Watabe AM, Utsunomiya K, Kato F - Mol Pain (2013)

Bottom Line: The analgesic effect of DLX was ified by the prior administration of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg, i.p.), which drastically eliminated dopamine-beta-hydroxylase- and norepinephrine transporter-immunopositive fibers in the lumbar spinal dorsal horn and significantly reduced the noradrenaline content in the lumbar spinal cord.The treatment with DSP-4 alone markedly lowered the nociceptive threshold in vehicle-treated non-diabetic rats; however, this pro-nociceptive effect was occluded in STZ-treated diabetic rats.DLX might exert its analgesic effect by selective enhancement of noradrenergic signals, thus counteracting this situation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, Jikei University School of Medicine, Minato, Tokyo 105-8461, Japan. fusao@jikei.ac.jp.

ABSTRACT

Background: Painful diabetic neuropathy (PDN) is a serious complication of diabetes mellitus that affects a large number of patients in many countries. The molecular mechanisms underlying the exaggerated nociception in PDN have not been established. Recently, duloxetine (DLX), a serotonin and noradrenaline re-uptake inhibitor, has been recommended as one of the first-line treatments of PDN in the United States Food and Drug Administration, the European Medicines Agency and the Japanese Guideline for the Pharmacologic Management of Neuropathic pain. Because selective serotonin re-uptake inhibitors show limited analgesic effects in PDN, we examined whether the potent analgesic effect of DLX contributes toward improving the pathologically aberrant noradrenaline homeostasis in diabetic models.

Results: In streptozotocin (STZ) (50 mg/kg, i.v.)-induced diabetic rats that exhibited robust mechanical allodynia and thermal hyperalgesia, DLX (10 mg/kg, i.p.) significantly and markedly increased the nociceptive threshold. The analgesic effect of DLX was ified by the prior administration of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg, i.p.), which drastically eliminated dopamine-beta-hydroxylase- and norepinephrine transporter-immunopositive fibers in the lumbar spinal dorsal horn and significantly reduced the noradrenaline content in the lumbar spinal cord. The treatment with DSP-4 alone markedly lowered the nociceptive threshold in vehicle-treated non-diabetic rats; however, this pro-nociceptive effect was occluded in STZ-treated diabetic rats. Furthermore, STZ-treated rats exhibited a higher amount of dopamine-beta-hydroxylase- and norepinephrine transporter-immunopositive fibers in the dorsal horn and noradrenaline content in the spinal cord compared to vehicle-treated rats.

Conclusions: Impaired noradrenaline-mediated regulation of the spinal nociceptive network might underlie exaggerated nociception in PDN. DLX might exert its analgesic effect by selective enhancement of noradrenergic signals, thus counteracting this situation.

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Effects of DSP-4 on analgesic effects of DLX in STZ-treated rats. Effects of DLX treatment on thermal hyperalgesia (A) and mechanical allodynia (B) in the rats treated with STZ (a) and vehicle (b) at 6 weeks after STZ injection. The control rats received equal volumes of distilled water (DW) instead of DLX. Thermal hyperalgesia was assessed at 60 min before (pre-DLX or DW, white columns) and 60 min after injection of DLX (post-DLX, dark gray columns) or DW (post-DW, light gray columns). Mechanical allodynia was assessed at 30 min before (pre-DLX or DW) and 90 min after injection of DLX (post-DLX) or DW (post-DW). Circles represent the values at pre-DLX and post-DLX (or DW) obtained from each rat. Bars indicate the mean values at pre-DLX and post-DLX (or DW). Each experimental group was composed of 5 rats. The differences in the values of pre-DLX and post-DLX were compared by Wilcoxon signed-rank test. (c) Change in paw withdrawal latency (A) and threshold (B) by DLX in the rats treated with STZ and vehicle. Change in paw withdrawal latency and threshold by DLX (y-axis for Ac and Bc) was calculated as the value of post-DLX divided by the value of pre-DLX. The mean ± SEM values of 5 rats for each experimental group are shown. The differences in the values were compared using the Mann–Whitney U-test.
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Figure 3: Effects of DSP-4 on analgesic effects of DLX in STZ-treated rats. Effects of DLX treatment on thermal hyperalgesia (A) and mechanical allodynia (B) in the rats treated with STZ (a) and vehicle (b) at 6 weeks after STZ injection. The control rats received equal volumes of distilled water (DW) instead of DLX. Thermal hyperalgesia was assessed at 60 min before (pre-DLX or DW, white columns) and 60 min after injection of DLX (post-DLX, dark gray columns) or DW (post-DW, light gray columns). Mechanical allodynia was assessed at 30 min before (pre-DLX or DW) and 90 min after injection of DLX (post-DLX) or DW (post-DW). Circles represent the values at pre-DLX and post-DLX (or DW) obtained from each rat. Bars indicate the mean values at pre-DLX and post-DLX (or DW). Each experimental group was composed of 5 rats. The differences in the values of pre-DLX and post-DLX were compared by Wilcoxon signed-rank test. (c) Change in paw withdrawal latency (A) and threshold (B) by DLX in the rats treated with STZ and vehicle. Change in paw withdrawal latency and threshold by DLX (y-axis for Ac and Bc) was calculated as the value of post-DLX divided by the value of pre-DLX. The mean ± SEM values of 5 rats for each experimental group are shown. The differences in the values were compared using the Mann–Whitney U-test.

Mentions: DLX, one of the first-choice medications for PDN [5,17], is an inhibitor of 5-HT and NA transporters. The decreased latency to thermal stimulation (Figure 3Aa; compare “Saline” and “DSP-4”) and the lowered threshold for mechanical stimulation (Figure 3Ba) in STZ-treated animals were significantly increased by a single injection of DLX (10 mg/kg, ip), supporting its pain relieving effect in the STZ models of PDN [11-13]. DLX exerted no significant changes in vehicle-treated rats (Figure 3Ab and Bb, “Saline”). In contrast, in the STZ-treated rats that received DSP-4 injection, DLX exerted no significant effect on both the thermal and the mechanical thresholds (Figure 3Aa and Ba, “DSP-4”). This absence of a DLX effect in DSP-4-treated rats was also similarly observed in vehicle-treated rats (Figure 3Ab and Bb, “DSP-4”). In this series of study, we have measured the nocifensive behaviors before and after DLX administration. It is therefore possible to evaluate how DLX improved nociception in individual rats by normalizing the latency (thermal) and threshold (mechanical) after DLX injection by the values measured before DLX injection (Figure 3Ac and Bc). This allowed direct comparison of the efficacy of DLX between in the absence and presence of DSP-4-treatment. The normalized effects of DLX were almost 1.0 (i.e., almost no effect) in STZ-treated rats that received DSP-4 and in vehicle-treated rats with or without DSP-4 (Figure 3Ac and Bc). In contrast, the effects of DLX on both the thermal and the mechanical nocifensive behaviors were significantly greater in STZ-treated rats without DSP-4 injection than in the other groups.


Impaired noradrenaline homeostasis in rats with painful diabetic neuropathy as a target of duloxetine analgesia.

Kinoshita J, Takahashi Y, Watabe AM, Utsunomiya K, Kato F - Mol Pain (2013)

Effects of DSP-4 on analgesic effects of DLX in STZ-treated rats. Effects of DLX treatment on thermal hyperalgesia (A) and mechanical allodynia (B) in the rats treated with STZ (a) and vehicle (b) at 6 weeks after STZ injection. The control rats received equal volumes of distilled water (DW) instead of DLX. Thermal hyperalgesia was assessed at 60 min before (pre-DLX or DW, white columns) and 60 min after injection of DLX (post-DLX, dark gray columns) or DW (post-DW, light gray columns). Mechanical allodynia was assessed at 30 min before (pre-DLX or DW) and 90 min after injection of DLX (post-DLX) or DW (post-DW). Circles represent the values at pre-DLX and post-DLX (or DW) obtained from each rat. Bars indicate the mean values at pre-DLX and post-DLX (or DW). Each experimental group was composed of 5 rats. The differences in the values of pre-DLX and post-DLX were compared by Wilcoxon signed-rank test. (c) Change in paw withdrawal latency (A) and threshold (B) by DLX in the rats treated with STZ and vehicle. Change in paw withdrawal latency and threshold by DLX (y-axis for Ac and Bc) was calculated as the value of post-DLX divided by the value of pre-DLX. The mean ± SEM values of 5 rats for each experimental group are shown. The differences in the values were compared using the Mann–Whitney U-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4222693&req=5

Figure 3: Effects of DSP-4 on analgesic effects of DLX in STZ-treated rats. Effects of DLX treatment on thermal hyperalgesia (A) and mechanical allodynia (B) in the rats treated with STZ (a) and vehicle (b) at 6 weeks after STZ injection. The control rats received equal volumes of distilled water (DW) instead of DLX. Thermal hyperalgesia was assessed at 60 min before (pre-DLX or DW, white columns) and 60 min after injection of DLX (post-DLX, dark gray columns) or DW (post-DW, light gray columns). Mechanical allodynia was assessed at 30 min before (pre-DLX or DW) and 90 min after injection of DLX (post-DLX) or DW (post-DW). Circles represent the values at pre-DLX and post-DLX (or DW) obtained from each rat. Bars indicate the mean values at pre-DLX and post-DLX (or DW). Each experimental group was composed of 5 rats. The differences in the values of pre-DLX and post-DLX were compared by Wilcoxon signed-rank test. (c) Change in paw withdrawal latency (A) and threshold (B) by DLX in the rats treated with STZ and vehicle. Change in paw withdrawal latency and threshold by DLX (y-axis for Ac and Bc) was calculated as the value of post-DLX divided by the value of pre-DLX. The mean ± SEM values of 5 rats for each experimental group are shown. The differences in the values were compared using the Mann–Whitney U-test.
Mentions: DLX, one of the first-choice medications for PDN [5,17], is an inhibitor of 5-HT and NA transporters. The decreased latency to thermal stimulation (Figure 3Aa; compare “Saline” and “DSP-4”) and the lowered threshold for mechanical stimulation (Figure 3Ba) in STZ-treated animals were significantly increased by a single injection of DLX (10 mg/kg, ip), supporting its pain relieving effect in the STZ models of PDN [11-13]. DLX exerted no significant changes in vehicle-treated rats (Figure 3Ab and Bb, “Saline”). In contrast, in the STZ-treated rats that received DSP-4 injection, DLX exerted no significant effect on both the thermal and the mechanical thresholds (Figure 3Aa and Ba, “DSP-4”). This absence of a DLX effect in DSP-4-treated rats was also similarly observed in vehicle-treated rats (Figure 3Ab and Bb, “DSP-4”). In this series of study, we have measured the nocifensive behaviors before and after DLX administration. It is therefore possible to evaluate how DLX improved nociception in individual rats by normalizing the latency (thermal) and threshold (mechanical) after DLX injection by the values measured before DLX injection (Figure 3Ac and Bc). This allowed direct comparison of the efficacy of DLX between in the absence and presence of DSP-4-treatment. The normalized effects of DLX were almost 1.0 (i.e., almost no effect) in STZ-treated rats that received DSP-4 and in vehicle-treated rats with or without DSP-4 (Figure 3Ac and Bc). In contrast, the effects of DLX on both the thermal and the mechanical nocifensive behaviors were significantly greater in STZ-treated rats without DSP-4 injection than in the other groups.

Bottom Line: The analgesic effect of DLX was ified by the prior administration of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg, i.p.), which drastically eliminated dopamine-beta-hydroxylase- and norepinephrine transporter-immunopositive fibers in the lumbar spinal dorsal horn and significantly reduced the noradrenaline content in the lumbar spinal cord.The treatment with DSP-4 alone markedly lowered the nociceptive threshold in vehicle-treated non-diabetic rats; however, this pro-nociceptive effect was occluded in STZ-treated diabetic rats.DLX might exert its analgesic effect by selective enhancement of noradrenergic signals, thus counteracting this situation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, Jikei University School of Medicine, Minato, Tokyo 105-8461, Japan. fusao@jikei.ac.jp.

ABSTRACT

Background: Painful diabetic neuropathy (PDN) is a serious complication of diabetes mellitus that affects a large number of patients in many countries. The molecular mechanisms underlying the exaggerated nociception in PDN have not been established. Recently, duloxetine (DLX), a serotonin and noradrenaline re-uptake inhibitor, has been recommended as one of the first-line treatments of PDN in the United States Food and Drug Administration, the European Medicines Agency and the Japanese Guideline for the Pharmacologic Management of Neuropathic pain. Because selective serotonin re-uptake inhibitors show limited analgesic effects in PDN, we examined whether the potent analgesic effect of DLX contributes toward improving the pathologically aberrant noradrenaline homeostasis in diabetic models.

Results: In streptozotocin (STZ) (50 mg/kg, i.v.)-induced diabetic rats that exhibited robust mechanical allodynia and thermal hyperalgesia, DLX (10 mg/kg, i.p.) significantly and markedly increased the nociceptive threshold. The analgesic effect of DLX was ified by the prior administration of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg, i.p.), which drastically eliminated dopamine-beta-hydroxylase- and norepinephrine transporter-immunopositive fibers in the lumbar spinal dorsal horn and significantly reduced the noradrenaline content in the lumbar spinal cord. The treatment with DSP-4 alone markedly lowered the nociceptive threshold in vehicle-treated non-diabetic rats; however, this pro-nociceptive effect was occluded in STZ-treated diabetic rats. Furthermore, STZ-treated rats exhibited a higher amount of dopamine-beta-hydroxylase- and norepinephrine transporter-immunopositive fibers in the dorsal horn and noradrenaline content in the spinal cord compared to vehicle-treated rats.

Conclusions: Impaired noradrenaline-mediated regulation of the spinal nociceptive network might underlie exaggerated nociception in PDN. DLX might exert its analgesic effect by selective enhancement of noradrenergic signals, thus counteracting this situation.

Show MeSH
Related in: MedlinePlus