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Differential cross-tolerance between analgesia produced by alpha 2-adrenoceptor agonists and receptor subtype
1Department of Pharmacology, Louisiana State University Medical Center, New Orleans 70130.
Abstract:
Analgesic cross-tolerance between alpha 2-adrenoceptor and opioid receptor agonists was studied using the mouse tail-flick assay. Mice tolerant to clonidine (0.3 mg/kg s.c.) or xylazine (7 mg/kg s.c.) were cross-tolerant to morphine (5 mg/kg s.c.), nalorphine (70 mg/kg s.c.) and supraspinal [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO; 4 ng i.c.v.), but not trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl] benzeneacetamide methanesulfonate (U50,488; 5 mg/kg s.c.), spinal DAMGO (10 ng i.t.), supraspinal [D-Pen2,D-Pen5]enkephalin (DPDPE; 9 micrograms i.c.v.) or spinal DPDPE (700 ng i.t.). In the complimentary studies, mice tolerant to morphine and nalorphine were cross-tolerant to both of the alpha 2-adrenoceptor agonists, but U50,488 tolerant mice were not. The results suggest differential interactions between alpha 2-adrenoceptor and mu 1-, mu 2-, delta-, kappa 1- and kappa 3-opioid analgesic circuitry.
Insights
Alpha 2-adrenoceptor agonists and opioid agonists show cross-tolerance, suggesting shared pathways in pain relief. However, this interaction is specific and does not involve all opioid receptor subtypes.
Area of Science:
- Pharmacology
- Neuroscience
- Pain Research
Background:
- Opioid and alpha 2-adrenoceptor agonists are used for pain management.
- Understanding cross-tolerance between these drug classes can reveal insights into shared analgesic mechanisms.
Purpose of the Study:
- To investigate the analgesic cross-tolerance between alpha 2-adrenoceptor agonists and various opioid receptor agonists in mice.
Main Methods:
- The mouse tail-flick assay was used to assess analgesic effects.
- Tolerance was induced using clonidine or xylazine, and cross-tolerance was tested with different opioid agonists (morphine, nalorphine, DAMGO, U50,488, DPDPE) administered supraspinally or spinally.
Main Results:
- Mice tolerant to alpha 2-adrenoceptor agonists (clonidine, xylazine) showed cross-tolerance to mu- and delta-opioid agonists (morphine, nalorphine, supraspinal DAMGO) but not kappa-opioid agonists (U50,488, spinal DAMGO, DPDPE).
- Mice tolerant to morphine and nalorphine were cross-tolerant to alpha 2-adrenoceptor agonists, but not to U50,488.
Conclusions:
- The findings indicate differential interactions between alpha 2-adrenoceptor and specific opioid receptor subtypes (mu 1, mu 2, delta) in mediating analgesia.
- Kappa opioid receptors appear to be less involved in this observed cross-tolerance phenomenon.