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Abstract Background Previous studies have demonstrated that intrathecal administration of the substance P amino-terminal metabolite substance P1-7 (SP1-7) and its C-terminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP1-7 and endomorphin-2, i.e. Phe-Phe amide, using the tail-flick test and von Frey filament test in diabetic and non-diabetic mice. Results Intrathecal treatment with the dipeptide increased the tail-flick latency in both diabetic and non-diabetic mice. This effect of Phe-Phe amide was significantly greater in diabetic mice than non-diabetic mice. The Phe-Phe amide-induced antinociceptive effect in both diabetic and non-diabetic mice was reversed by the σ1 receptor agonist (+)-pentazocine. Moreover, Phe-Phe amide attenuated mechanical allodynia in diabetic mice, which was reversible by (+)-pentazocine. The expression of spinal σ1 receptor mRNA and protein did not differ between diabetic mice and non-diabetic mice. On the other hand, the expression of phosphorylated extracellular signal-regulated protein kinase 1 (ERK1) and ERK2 proteins was enhanced in diabetic mice. (+)-Pentazocine caused phosphorylation of ERK1 and ERK2 proteins in non-diabetic mice, but not in diabetic mice. Conclusions These results suggest that the spinal σ1 receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by Phe-Phe amide.

Abstract: Renal ischemia produces sympathoexcitation, which is responsible for the development of ischemic acute kidney injury. Stimulation of central opioid receptors activates the renal sympathetic nerve. The present study examined the effect of an opioid receptor antagonist naloxone on the ischemia/reperfusion-induced renal dysfunction in mice. Blood urea nitrogen (BUN) and plasma creatinine increased 24 h after the renal ischemia/reperfusion. Intraperitoneal or intracerebroventricular, but not intrathecal, pretreatment with naloxone suppressed the renal ischemia/reperfusion-induced increases in BUN and plasma creatinine. This effect of naloxone was reversed by subcutaneous pretreatment with morphine. Selective MOP receptor antagonist β-funaltrexamine (FNA) also suppressed the renal ischemia/reperfusion-induced increases in BUN and plasma creatinine. Moreover, tyrosine hydroxylase expression in the renal tissue increased 24 h after renal ischemia/reperfusion, which was abolished by intraperitoneal or intracerebroventricular pretreatment with naloxone and FNA. Immunohistochemical experiments revealed a significant increase in the number of the Fos family proteins (c-Fos, FosB, Fra-1, and Fra-2) positive cells in the paraventricular nucleus of hypothalamus and supraoptic nucleus 24 h after the renal ischemia/reperfusion. Intracerebroventricular pretreatment with naloxone attenuated the renal ischemia/reperfusion-induced increase in the number of the Fos family proteins positive cells in these areas. Finally, we observed that i.c.v. pretreatment with antiserum against β-endorphin also suppressed the increased blood urea and plasma creatinine. These results suggest that the blockade of central opioid receptors can attenuate the ischemic acute kidney injury through the inhibition of renal sympathoexcitation. The central opioid receptors may thus be a new target for the treatment of ischemic organ failures. [Copyright &y& Elsevier]

Abstract: We previously demonstrated that intrathecal treatment with substance P metabolite substance P1–7 induced anti-hyperalgesia in diabetic mice. In the present study, we have used a synthetic analog of this peptide, the substance P1–7 amide, showing higher binding affinitiy than the native heptapeptide, for studies of the tail-flick response in diabetic and non-diabetic mice. Intrathecal injection of substance P1–7 amide produced prolongation of the tail-flick latency in both diabetic and non-diabetic mice, an effect that was more pronounced in diabetic mice than non-diabetic mice. Moreover, the observed antinociceptive potency of the substance P1–7 amide was higher in both diabetic and non-diabetic mice in comparison with the native substance P1–7. The antinociceptive effect of substance P1–7 amide was reversed by naloxone but not by the selective opioid receptor antagonist β-funaltrexamine, naltrindole or nor-binaltorphimine, selective for the μ-, δ- or κ-opioid receptor, respectively. In addition, the antinociceptive effect induced by substance P1–7 amide was partly reversed by the σ1 receptor agonist (+)-pentazocine, suggesting a possible involvement of the σ1 receptor for the action of this peptide. These results suggest that the actions of substance P1–7 amide mimic the effects of the native substance P fragment but with higher potency and that the mechanisms for its action may involve the σ1 receptor system. [ABSTRACT FROM AUTHOR]

Abstract: We have recently explored the role of the tachykinin substance P neuroactive fragment substance P1–7 in the mediation of anti-inflammatory effects using a blister model in the rat paw (Wiktelius et al., 2006). We observed that this heptapeptide induced a dose-dependent inhibitory effect on the substance P-induced response, which was reversible by the non-selective opioid receptor antagonist naloxone. In the present study, we examined the ability of substance P1–7 to induce antihyperalgesic effects in streptozotocin-induced diabetic mice. We found that the substance P fragment strongly and dose-dependently produced antihyperalgesia in diabetic mice. This effect was reversed by naloxone but not by the selective opioid receptor antagonist β-funaltrexamine, naltrindole or nor-binaltorphimine, selective for the µ-, δ- or κ-opioid receptor, respectively. In addition, the antihyperalgesic effect induced by substance P1–7 was partly reversed by a σ1 receptor agonist (+)-pentazocine, but not a σ1 receptor antagonist BD1047 ([2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(diamino)ethylamine), suggesting that involvement of the naloxone-sensitive σ-receptor for the action of the SP related heptapeptides. These results suggest that hyperalgesia in diabetic mice may be, in part, due to the enhanced endogenous σ1 receptor systems in the spinal cord. [Copyright &y& Elsevier]

Beta-arrestins have been suggested to regulate μ-, δ-, and κ-opioid receptor-mediated responses. In the present study, we examined the effects of pretreatment with β-arrestin-2 antibody on tail-flick inhibition induced by opioid receptor agonists in the mouse spinal cord. Intrathecal (i.t.) pretreatment with β-arrestin-2 antibody potentiated the antinociception induced by i.t.-administered μ-opioid receptor agonists [d-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO) and endomorphin-1, but not endomorphin-2, the δ-opioid receptor agonist [d-Ala2]deltorphin II or the κ-opioid receptor agonist U50,488H. The present result suggests that β-arrestin-2 may tonically down-regulate a selected population of μ-opioid receptors activated by endomorphin-1 or DAMGO in the mouse spinal cord. [Copyright &y& Elsevier]