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Antisense oligodeoxynucleotide to a delta-opioid receptor blocks the antinociception induced by cold water swimming
H Mizoguchi1, M Narita, H Nagase
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Abstract:
The type of opioid receptors in the spinal cord involved in antinociception induced by cold water swimming (CWS) was studied in male ICR mice. Mice were submitted to CWS for 3 min and antinociception was measured 7 min after the CWS by the tail-flick test. Intrathecal (i.t.) injection of naltrindole (NTI, 5 micrograms) which blocked i.t. DPDPE ([D-Pen2,D-Pen5]en-kephalin, 5 micrograms)-induced antinociception, blocked the CWS-induced antinociception. On the other hand, i.t. injection of CTOP (D-Phe-Cys-Try-D-Try-Orn-Thr-Pen-Thr-NH2, 50 ng) and norbinaltorphimine (nor-BNI, 5 micrograms) which blocked i.t. DAMGO ([D-Ala2,NHPhe4,Gly-ol]enkephalin, 10 ng)- and U50,488H (trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide, 75 micrograms)-induced antinociception, respectively, did not block CWS-induced antinociception. Intrathecal pretreatment with antisense oligodeoxynucleotide to delta-opioid receptor mRNA (delta-AS oligo, 163 pmol) once a day for 1 to 3 days caused a time-dependent attenuation of CWS-induced antinociception. delta-AS at doses from 1.6 to 163 pmol pretreated i.t. for 3 days caused a dose-dependent blockade of CWS-induced antinociception. However, i.t. pretreatment with mismatch oligodeoxynucleotide (MM oligo, 163 pmol) for 3 days did not affect the CWS-induced antinociception. The results indicate that CWS-induced antinociception is mediated by the stimulation of delta-opioid receptors in the spinal cord.
Insights
Cold water swimming (CWS) triggers pain relief (antinociception) in mice. This effect is mediated by delta-opioid receptors in the spinal cord, as confirmed by blocking agents and antisense oligonucleotides.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Cold water swimming (CWS) is a known stimulus for pain relief (antinociception).
- The specific opioid receptor subtypes involved in CWS-induced antinociception within the spinal cord remain incompletely understood.
Purpose of the Study:
- To investigate the type of opioid receptors in the spinal cord responsible for antinociception induced by CWS.
- To elucidate the precise molecular mechanisms underlying CWS-mediated pain modulation.
Main Methods:
- Male ICR mice were subjected to CWS for 3 minutes, followed by antinociception measurement using the tail-flick test.
- Intrathecal administration of specific opioid receptor antagonists (naltrindole, CTOP, norbinaltorphimine) and antisense oligodeoxynucleotides targeting delta-opioid receptor mRNA was employed.
- The effects of these interventions on CWS-induced antinociception were systematically evaluated.
Main Results:
- Intrathecal naltrindole blocked CWS-induced antinociception, while CTOP and norbinaltorphimine did not.
- Antisense oligodeoxynucleotides against delta-opioid receptor mRNA dose-dependently and time-dependently attenuated CWS-induced antinociception.
- Mismatch oligodeoxynucleotides did not affect CWS-induced antinociception, confirming the specificity of the antisense effect.
Conclusions:
- The findings strongly indicate that CWS-induced antinociception is primarily mediated by the activation of delta-opioid receptors located in the spinal cord.
- This study identifies a specific role for delta-opioid receptors in the pain-modulating effects of CWS.