Elsevier

Neuropeptides

Volume 32, Issue 5, October 1998, Pages 411-415
Neuropeptides

Intrathecal administration of p-hydroxymercuribenzoate or phosphoramidon/bestatin-combined induces antinociceptive effects through different opioid mechanisms

https://doi.org/10.1016/S0143-4179(98)90064-6Get rights and content

Abstract

The antinociceptive effect of intrathecally (i.t.) administered protease inhibitors was tested against capsaicin (800 ng) injected into the dorsal surface of a hindpaw. Both p-hydroxymercuribenzoate (2–8 nmol), a cysteine protease inhibitor, and phosphoramidon (1–4 nmol), an endopeptidase 24.11 inhibitor in the presence of bestatin (0.25 nmol) an aminopeptidase inhibitor, administered i.t. 60 min prior to the injection of capsaicin produced a dose-dependent reduction of the capsaicin-induced paw licking and biting response. p-Hydroxymercuribenzoate (4 nmol)-induced antinociception was significantly antagonized by nor-binaltorphimine, a selective κ-opioid receptor antagonist, but not by naltrindole, a selective δ-opioid receptor antagonist. On the other hand, phosphoramidon (4 nmol) /bestatin-induced antinociception was significantly antagonized by naltrindole, but not by nor-binaltorphimine. The results indicate that the antinociceptive effect of p-hydroxymercuribenzoate may be due to the inhibition of a cysteine protease degrading endogenous dynorphins whereas phosphoramidon in the presence of bestatin blocks the degradation of enkephalins.

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    Moreover, it was observed that the analgesic effect of phosphoramidon in combination with bestatin have been antagonized by the selective δ-opioid receptor antagonist naltrindole, but not by κ-opioid receptor antagonist nor-binaltorphimine. This may suggest that antinociception induced by phosphoramidon is not directly connected to the inhibition of DCEs, but rather blocks the degradation of endogenous enkephalins in the spinal cord of mouse (Tan-No et al., 1996, 1997, 1998). The ability of amastatin, captopril and/or phosphoramidon in potentiating the inhibitory effect of dynorphin A1–8 on the electrically evoked contractions of guinea-pig ileum, mouse vas deferens and rabbit vas deferens, was also reported in this study.

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    We have examined the effect of various protease inhibitors on the functions in the central nervous system (CNS). The findings regarding cysteine protease inhibitors that have been found so far are described as follows: (1) p-hydroxymercuribenzoate (PHMB), a general cysteine protease inhibitor, and Boc-Tyr-Gly-NHO-Bz (BYG-Bz), a representative of a novel class of cysteine protease inhibitors, when co-administered with dynorphin A or dynorphin B, significantly prolong antinociception induced by intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of these dynorphins in the mouse formalin and capsaicin tests (Tan-No et al., 1996, 2001, 2005a); (2) i.t.-administered PHMB produces antinociceptive effect in capsaicin test through the inhibition of endogenous dynorphin degradation (Tan-No et al., 1998); (3) i.t.-administered N-ethylmaleimide, another cysteine protease inhibitor, produces nociceptive behavior through the inhibition of endogenous dynorphin degradation in uninjured mice (Tan-No et al., 2005b); (4) N-ethylmaleimide and BYG-Bz suppress the development of antinociceptive tolerance to morphine, presumably through the inhibition of dynorphin degradation when administered i.t. 5 min before each morphine pretreatment during the induction (Tan-No et al., 2008). These observations indicate that cysteine protease inhibitors modulate CNS pathways engaged in pain transmission and morphine tolerance, through the inhibition of endogenous dynorphin degradation.

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    Once this has been done, dynorphin A could induce allodynia and hyperalgesia to protect the injured area from further damage by immobilizing the injured limb/part of the body and this action is mediated through the NMDA receptors. Differential effects of cysteine protease inhibitors mediated through the dynorphin system support the notion that endogenous dynorphins play antinociceptive and pronociceptive roles in an acute pain state (Tan‐No et al., 1998) and uninjured animals (Tan‐No et al., 2005b), respectively. A consensus of different studies appears to be that the spinal dynorphin system plays an inhibitory role in nociceptive transmission mediated through the κ‐opioid receptor in an acute pain state, and a facilitative role mediated through an NMDA receptor mechanism in a chronic pain state when the κ‐opioid receptor became tolerant due to sustained activation by endogenous dynorphins (Xu et al., 2004).

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