Spinorphin, an Endogenous Inhibitor of Enkephalin-Degrading Enzymes, Potentiates Leu-Enkephalin-Induced Anti-allodynic and Antinociceptive Effects in Mice

Honda, Motoko; Okutsu, Hiroko; Matsuura, Tomoyuki; Miyagi, Tomohiro; Yamamoto, Yasutake; Hazato, Tadahiko; Ono, Hideki

doi:10.1254/jjp.87.261

Cited by 26 publications

(12 citation statements)

References 24 publications

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“…In fact, three endogenous inhibitors of aminopeptidase and neutral endopeptidase have been found: spinorphin -LVVYPWT (Nishimura and Hazato, 1993), sialorphin -QHNPR (Rougeot et al, 2003) and opiorphin -QRFSR (Wisner et al, 2006). The release of these peptidase-inhibiting peptides appears to play a role in pain control, since sialorphin and opiorphin have analgesic properties, while spinorphin increased the antinociception produced by Leu-enkephalin (Honda et al, 2001). Hence, the instances of analgesia mediated by spinal opioid receptors mentioned above may involve the simultaneous release of opioids and peptidase-inhibiting peptides.…”

Section: Discussionmentioning

confidence: 99%

Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce μ-opioid receptor internalization in the presence of peptidase inhibitors

et al. 2008

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The internalization of μ-opioid receptors (MORs) provides an ideal way to locate areas of opioid peptide release. We used this method to study opioid release in the spinal cord evoked by noxious stimuli in anesthetized rats. Previous studies have shown that opioids released in the spinal cord produce MOR internalization only when they are protected from peptidase degradation. Accordingly, rats were implanted with chronic intrathecal catheters that were used to inject a mixture of peptidase inhibitors (amastatin, captopril and phosphoramidon) onto the lumbar spinal cord. Five minutes later, a noxious stimulus was delivered to the paw. Lumbar spinal segments were double-stained with antibodies against MORs and neurokinin 1 receptors (NK1Rs) using immunofluorescence. Mechanical stimulation of the hindpaw consisted of repeated 10 sec clamps with a hemostat for 10 min. In the ipsilateral dorsal horn, the stimulus produced abundant NK1R internalization in segments L3-L6, and a more modest but significant MOR internalization in segments L5 and L6. In the contralateral dorsal horn, NK1R was substantially lower and MOR internalization was negligible. The same mechanical stimulus applied to a forepaw did not produce NK1R or MOR internalization in the lumbar spinal cord. Thermal stimulation consisted of immersing a hindpaw in water at 52 °C for 2 min. It produced substantial NK1R internalization ipsilaterally in segment L6, but no MOR internalization. These results show that mechanical stimulation induces segmental opioid release, i.e., in the dorsal horn receiving the noxious signals and not in other spinal segments.

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Section: Discussionmentioning

confidence: 99%

Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce μ-opioid receptor internalization in the presence of peptidase inhibitors

et al. 2008

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“…Three endogenous inhibitors of aminopeptidases and neutral endopeptidase (two of the enzymes that degrade enkephalin) have been identified so far: spinorphin (LVVYPWT), isolated from bovine spinal cord (Nishimura and Hazato, 1993); sialorphin (QHNPR), identified in the rat submandibular gland and prostate (Rougeot et al, 2003), and opiorphin (QRFSR), isolated from human saliva (Wisner et al, 2006). Spinorphin increases the antinociceptive effects of Leu-enkephalin (Honda et al, 2001), and sialorphin and opiorphin have analgesic properties. Sialorphin secretion is stimulated by stress (Rougeot et al, 2003), a condition known to produce opioid-mediated analgesia (Lewis et al, 1981).…”

Section: Physiological Significance Of Opioid Degradation By Peptidasesmentioning

confidence: 99%

Comparing analgesia and μ-opioid receptor internalization produced by intrathecal enkephalin: Requirement for peptidase inhibition

et al. 2007

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Opioid receptors in the spinal cord produce strong analgesia, but the mechanisms controlling their activation by endogenous opioids remain unclear. We have previously shown in spinal cord slices that peptidases preclude mu-opioid receptor (MOR) internalization by opioids. Our present goals were to investigate whether enkephalin-induced analgesia is also precluded by peptidases, and whether it is mediated by MORs or delta-opioid receptors (DORs). Tail-flick analgesia and MOR internalization were measured in rats injected intrathecally with Leu-enkephalin and peptidase inhibitors. Without peptidase inhibitors, Leu-enkephalin produced neither analgesia nor MOR internalization at doses up to 100 nmol, whereas with peptidase inhibitors it produced analgesia at 0.3 nmol and MOR internalization at 1 nmol. Leu-enkephalin was 10 times more potent to produce analgesia than to produce MOR internalization, suggesting that DORs were involved. Selective MOR or DOR antagonists completely blocked the analgesia elicited by 0.3 nmol Leu-enkephalin (a dose that produced little MOR internalization), indicating that it involved these two receptors, possibly by an additive or synergistic interaction. The selective MOR agonist endomorphin-2 produced analgesia even in the presence of a DOR antagonist, but at doses substantially higher than Leu-enkephalin. Unlike Leu-enkephalin, endomorphin-2 had the same potencies to induce analgesia and MOR internalization. We concluded that low doses of enkephalins produce analgesia by activating both MORs and DORs. Analgesia can also be produced exclusively by MORs at higher agonist doses. Since peptidases prevent the activation of spinal opioid receptors by enkephalins, the coincident release of opioids and endogenous peptidase inhibitors may be required for analgesia.

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“…Intraplantar administration of neprilysin and aminopeptidase N inhibitors was found to induce analgesia in a rat hindpaw model of inflammatory pain through DOP, MOP, and KOP. Earlier, Honda et al [19] proved that for simultaneous intracerebroventricular (i.c.v.) [16] Notably, administration of a mixed enkephalinase inhibitor, RB101, showed no antinociceptive tolerance and no physical dependence compared with morphine in animal studies.…”

Section: Resultsmentioning

confidence: 99%

Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

et al. 2018

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Irritable bowel syndrome (IBS) is a chronic disease characterized by abdominal pain and changes in bowel habits. Patients with IBS comprise a significant portion of attendants at the outpatient clinics. Targeting intestinal opioid receptors was found successful in alleviating pain and diarrhea-two major symptoms of IBS. In this study, we aimed to evaluate a novel potential pharmacological option: the use of enkephalinase inhibitors in therapy of visceral pain occurring in the course of IBS. We thus assessed the antinociceptive efficacy of enkephalins: Leu-enkephalin and Met-enkephalin, and enkephalinase inhibitors: opiorphin and sialorphin in the mouse model of visceral pain induced by colorectal distension. Leu-enkephalin, Met-enkephalin, and sialorphin, but not opiorphin, at the dose of 1 mg/kg injected subcutaneously potently decreased the visceromotor response to colon distension as compared to control. To conclude, enkephalinase inhibitors are worth being considered as potential therapeutics in patients with chronic abdominal pain and/or changed bowel habits, that is, suffering from IBS.

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Spinorphin, an Endogenous Inhibitor of Enkephalin-Degrading Enzymes, Potentiates Leu-Enkephalin-Induced Anti-allodynic and Antinociceptive Effects in Mice

Cited by 26 publications

References 24 publications

Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce μ-opioid receptor internalization in the presence of peptidase inhibitors

Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce μ-opioid receptor internalization in the presence of peptidase inhibitors

Comparing analgesia and μ-opioid receptor internalization produced by intrathecal enkephalin: Requirement for peptidase inhibition

Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

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