Elsevier

Neuroscience

Volume 99, Issue 2, 11 September 2000, Pages 327-331
Neuroscience

Role of the phosphatidylinositol-specific phospholipase C pathway in δ-opioid receptor-mediated antinociception in the mouse spinal cord

https://doi.org/10.1016/S0306-4522(00)00202-5Get rights and content

Abstract

Stimulation of δ-opioid receptors has been shown to activate phospholipase C via the activation of G-proteins in vitro. The present study was designed to determine, with the tail-flick method, whether the stimulatory effect of δ-opioid receptor agonists on phospholipase C and inositol lipid turnover participates in the mechanisms of the δ-opioid receptor-mediated antinociception in the mouse spinal cord. Intrathecal pretreatment with the phospholipase C inhibitors neomycin and U73122, which produced no changes in the basal tail-flick latencies when they were injected alone, significantly attenuated the antinociception induced by intrathecal administration of the selective δ-opioid receptor agonist [d-Ala2]deltorphin II in mice. The selective phosphatidylinositol-specific phospholipase C inhibitor ET-18-OCH3 inhibited the antinociception induced by intrathecal administration of [d-Ala2]deltorphin II in a dose-dependent manner. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, the antinociception induced by intrathecal administration of [d-Ala2]deltorphin II was significantly reduced. Co-administration of d-myo-inositol-1,4,5-trisphosphate restored the [d-Ala2]deltorphin II-induced antinociception in LiCl-pretreated mice. On the other hand, intrathecal pretreatment with the selective protein kinase C inhibitor calphostin C, but not the protein kinase A inhibitor KT5720, resulted in a dose-dependent enhancement of the [d-Ala2]deltorphin II-induced antinociception.

These results indicate a potential role for the phospholipase C–inositol-1,4,5-trisphosphate pathway in the expression of δ-opioid receptor-mediated antinociception in the mouse spinal cord. Furthermore, activation of protein kinase C by the stimulation of δ-opioid receptors may constitute a significant pathway involved in negative modulation of spinal δ-opioid receptor-mediated antinociception.

Section snippets

Animals

Male Institute of Cancer Research mice weighing 23–27 g (SASCO, Omaha, NE, USA) were used. All experiments were approved by and conformed to the guidelines of the Medical College of Wisconsin Animal Care Committee. Every effort was made to minimize the numbers and any suffering of animals used in the following experiments. Animals were housed five per cage in a room maintained at 22±0.5°C with an alternating 12-h light–dark cycle. Food and water were available ad libitum. Animals were used only

Effects of intrathecal pretreatment with the phospholipase C inhibitors, neomycin, U73122 and ET-18-OCH3, on antinociception induced by intrathecal administration of [d-Ala2]deltorphin II

The experiments were designed to determine whether PLC could be involved in [d-Ala2]deltorphin II-induced antinociception in the spinal cord. Neomycin and U73122 are selective inhibitors of PLC.20., 38. ET-18-OCH3 is a selective inhibitor of phosphatidylinositol (PI)-specific PLC.27 Groups of mice were pretreated intrathecally with saline, neomycin (5.5, 11.0 or 22.0 nmol; 5, 10 or 20 μg), vehicle (50% DMSO in 0.9% NaCl), U73122 (2.7, 4.0 or 5.4 nmol; 1.25, 1.88 or 2.50 μg) or ET-18-OCH3 (0.095,

Discussion

Recent work with cell lines has demonstrated that some δ-opioid receptors may be linked to the PLC pathway. In the mouse periaqueductal gray matter and spinal cord, δ-opioid receptor agonists, such as [d-Ala2]deltorphin II and [d-Pen2,5]enkephalin, cause an increase in inositol phosphate accumulation.23., 25. These findings support the idea that the PLC pathway may, at least in part, contribute to the antinociception induced by δ-opioid receptor agonists.

Several PLC inhibitors are currently

Conclusions

The present study reveals a potential role for the PLC–IP3 pathway in the expression of antinociceptive responses regulated by spinal δ-opioid receptors in the mouse. Furthermore, it is most likely that concomitant activation of PKC by δ-opioids results in an autoinhibitory feedback action on the spinal δ-opioid receptor system to produce antinociception.

Acknowledgements

We thank Ms Michiko Narita for technical assistance. This work was mainly supported by US Public Health Service Grant DA 03811 from the National Institute on Drug Abuse, National Institutes of Health.

References (38)

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