Abstract
We have previously demonstrated that the antinociception induced by either endomorphin-1 or endomorphin-2 given supraspinally is mediated by the stimulation of μ-opioid receptors. However, the antinociception induced by endomorphin-2 given supraspinally contains additional components, which are mediated by the spinal release of dynorphin A (1–17) acting on κ-opioid receptors and the spinal release of [Met5]enkephalin acting on δ2-opioid receptors in the spinal cord. The present studies were performed to determine whether there are any differential effects on the tail-flick inhibition induced by endomorphin-1 and endomorphin-2 given intrathecally (i.t.) in mice. Endomorphin-1 or endomorphin-2 given i.t. inhibited the tail-flick response in a dose-dependent manner. The tail-flick inhibition induced by endomorphin-1 was blocked by i.t. pretreatment with μ-opioid receptor antagonistd-Phe-Cys-Tyr-d-Try-Orn-Thr-Pen-Thr-NH2(CTOP), but not κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI), δ1-opioid receptor antagonist 7-benzylidene naltrexamine (BNTX), or δ2-opioid receptor antagonist naltriben (NTB). In contrast, the tail-flick inhibition induced by endomorphin-2 given i.t. was blocked by i.t. pretreatment with CTOP or nor-BNI, but not BNTX or NTB. Intrathecal pretreatment with antiserum against dynorphin A (1–17), but not antiserum against [Met5]enkephalin, [Leu5]enkephalin, or β-endorphin, blocked the tail-flick inhibition induced by i.t.-administered endomorphin-2. None of these antisera attenuated the i.t.-administered endomorphin-1-induced tail-flick inhibition. It is concluded that the tail-flick inhibition induced by endomorphin-1 and endomorphin-2 given spinally is mediated by the stimulation of μ-opioid receptors. However, the tail-flick inhibition induced by spinally injected endomorphin-2 contains an additional component, which is mediated by the spinal release of dynorphin A (1–17) acting on κ-opioid receptors in the spinal cord. We propose that there are at least two different subtypes of μ-opioid receptors for endomorphin-1 and endomorphin-2 to produce antinociception in the spinal cord.
Footnotes
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This study was supported by Grant DA 03811 from the National Institutes of Health, National Institute on Drug Abuse (to L.F.T.). A preliminary report of some of these results was presented at the 30th Annual Meeting of the Neuroscience, New Orleans, LA, November 4–9, 2000 (Tseng et al., 2000b).
- Abbreviations:
- i.t.
- intrathecal
- 5-HT
- 5-hydroxytryptamine
- nor-BNI
- nor-binaltorphimine
- NTB
- naltriben
- BNTX
- 7-benzylidene naltrexamine
- CTOP
- d-Phe-Cys-Tyr-d-Try-Orn-Thr-Pen-Thr-NH2
- ODN
- oligodeoxynucleotide
- Received January 26, 2001.
- Accepted April 18, 2001.
- The American Society for Pharmacology and Experimental Therapeutics