TY - JOUR
T1 - The spinal antinociceptive effects of endomorphins in rats
T2 - Behavioral and G protein functional studies
AU - Xie, Hong
AU - Woods, James H.
AU - Traynor, John R.
AU - Ko, Mei Chuan
N1 - Funding Information:
Supported by US Public Health Service Grants DA-000254 & DA-013685, and Taiwan National Science Council Grant NSC-96-2413-H-004-019.
PY - 2008/6
Y1 - 2008/6
N2 - BACKGROUND: Endomorphin-1 and endomorphin-2 are endogenous peptides that are highly selective for μ-opioid receptors. However, studies of their functional efficacy and selectivity are controversial. In this study, we systematically compared the effects of intrathecal (i.t.) administration of endomorphin-1 and -2 on nociception assays and G protein activation with those of [d-Ala2,N-Me-Phe4,Gly5-ol]- enkephalin (DAMGO), a highly effective peptidic μ-opioid receptor agonist. METHODS: Male Sprague-Dawley rats were used. Acute and inflammatory pain models were used to compare the duration and magnitude of antinociception. Agonist-stimulated [ 35S]GTPγS binding was used to observe the functional activity at the level of the receptor-G protein in both spinal cord and thalamic membranes. In addition, antagonists selective for each receptor type were used to verify the functional selectivity of endomorphins in the rat spinal cord. RESULTS: After i.t. administration, endomorphin-1 and -2 produced less antinociceptive effects than DAMGO in the model of acute pain. Concentration-response curves for DAMGO-, endomorphin-1-, and endomorphin-2-stimulated [35S]GTPγS binding revealed that both endomorphin-1 and -2 produced less G protein activation (i.e., approximately 50%-60%) than DAMGO did in the membranes of spinal cord and thalamus. In addition, i.t. endomorphin-induced antinociception was blocked by μ-opioid receptor selective dose of naltrexone (P < 0.05), but not by δ- and κ-opioid receptor antagonists, naltrindole and nor-binaltorphimine (P > 0.05). CONCLUSIONS: Endomorphins are partial agonists for G protein activation at spinal and thalamic μ-opioid receptors. Both in vivo and in vitro measurements together suggest that DAMGO is more effective than endomorphins. Spinal endomorphins' antinociceptive efficacy may range between 53% and 84% depending on the intensity and modality of the nociceptive stimulus.
AB - BACKGROUND: Endomorphin-1 and endomorphin-2 are endogenous peptides that are highly selective for μ-opioid receptors. However, studies of their functional efficacy and selectivity are controversial. In this study, we systematically compared the effects of intrathecal (i.t.) administration of endomorphin-1 and -2 on nociception assays and G protein activation with those of [d-Ala2,N-Me-Phe4,Gly5-ol]- enkephalin (DAMGO), a highly effective peptidic μ-opioid receptor agonist. METHODS: Male Sprague-Dawley rats were used. Acute and inflammatory pain models were used to compare the duration and magnitude of antinociception. Agonist-stimulated [ 35S]GTPγS binding was used to observe the functional activity at the level of the receptor-G protein in both spinal cord and thalamic membranes. In addition, antagonists selective for each receptor type were used to verify the functional selectivity of endomorphins in the rat spinal cord. RESULTS: After i.t. administration, endomorphin-1 and -2 produced less antinociceptive effects than DAMGO in the model of acute pain. Concentration-response curves for DAMGO-, endomorphin-1-, and endomorphin-2-stimulated [35S]GTPγS binding revealed that both endomorphin-1 and -2 produced less G protein activation (i.e., approximately 50%-60%) than DAMGO did in the membranes of spinal cord and thalamus. In addition, i.t. endomorphin-induced antinociception was blocked by μ-opioid receptor selective dose of naltrexone (P < 0.05), but not by δ- and κ-opioid receptor antagonists, naltrindole and nor-binaltorphimine (P > 0.05). CONCLUSIONS: Endomorphins are partial agonists for G protein activation at spinal and thalamic μ-opioid receptors. Both in vivo and in vitro measurements together suggest that DAMGO is more effective than endomorphins. Spinal endomorphins' antinociceptive efficacy may range between 53% and 84% depending on the intensity and modality of the nociceptive stimulus.
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U2 - 10.1213/ane.0b013e31817300be
DO - 10.1213/ane.0b013e31817300be
M3 - Article
C2 - 18499626
AN - SCOPUS:44649139859
VL - 106
SP - 1873
EP - 1881
JO - Anesthesia and Analgesia
JF - Anesthesia and Analgesia
SN - 0003-2999
IS - 6
ER -