Abstract
This study examined the effects of intrathecally (i.t.) administeredmu and delta opioid receptor agonists on the flinching behavior and the expression of Fos-like immunoreactivity (Fos-LI) in the spinal cord elicited by s.c. injection of 5% formalin in one hindpaw of the rat. Intrathecal pretreatment with either thedelta-1 opioid receptor agonist [d-Pen2,5]enkephalin (DPDPE) or thedelta-2 opioid receptor agonist [d-Ala2,Glu4]deltorphin (DELT) produced a dose-dependent inhibition of flinching behavior in phase 1 and phase 2 that was antagonized by coadministration of thedelta-1 opioid receptor antagonist 7-benzylidinenaltrexone or the delta-2 opioid receptor antagonist Naltriben, respectively. Although i.t. pretreatment with 60 μg of DPDPE produced a small decrease in the numbers of Fos-LI neurons in laminae I, IIi and IIo, as well as laminae V and VI and laminae VII–X, i.t. pretreatment with 30 μg of DELT did not decrease the number of Fos-LI neurons in any region of the spinal cord. In contrast, i.t. pretreatment with an equieffective dose of themu opioid receptor agonist [d-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO) not only significantly decreased the number of flinches in phase 1 and phase 2, but also nearly completely prevented the expression of Fos-LI in all regions of the spinal cord. These effects were antagonized by pretreatment with the mu opioid receptor antagonistd-Phe-Cys-Tyr-d-Trp-Arg-Thr-Phe-Thr-NH2. The efficacy of i.t. administered DAMGO suggests that a direct spinal action contributes to the inhibition of noxious stimulus-evoked Fos-LI in the spinal cord produced by systemically administeredmu opioid receptor agonists such as morphine. The relative lack of effect of DPDPE or DELT suggests thatdelta opioid receptors do not modulate the early-immediate gene c-fos. Alternatively, becausedelta opioid receptor agonists inhibit synaptic transmission in the spinal cord by predominantly presynaptic mechanisms and do not hyperpolarize dorsal horn neurons, the excitatory inputs that persist in the presence of these agonists may be sufficient to activate the c-fos gene. Taken together, these results provide new evidence, at the level of a “third messenger,” that the antinociception produced by i.t. administration of deltaand mu opioid receptor agonists is mediated by different mechanisms.
Footnotes
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Send reprint requests to: Donna L. Hammond, Ph.D., Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Avenue MC 4028, Chicago, IL 60637.
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↵1 This work was supported by Public Health Service grants DA06736 (to D.L.H.) and DA08377 (to A.I.B.). These experiments were conducted under a protocol approved by the Institutional Animal Care and Use Committee of the University of Chicago and in accordance with the “Guide for Care and Use of Laboratory Animals” as published by the National Institutes of Health.
- Abbreviations:
- i.t.
- intrathecal(ly)
- i.c.v.
- intracerebroventricular
- Fos-LI
- Fos-like immunoreactive(ity)
- i.pl.
- intraplantar
- DPDPE
- [d-Pen2,5]enkephalin
- DELT
- [d-Ala2,Glu4]deltorphin
- BNTX
- 7-benzylidinenaltrexone
- NTB
- Naltriben
- DAMGO
- [d-Ala2,NMePhe4,Gly-ol5]enkephalin
- CTOP
- d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Phe-Thr-NH2
- CI-977
- (5R)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolindinyl)-1-oxaspiro[4,5]dec-8-yl]-4-benzofurnacetamide hydrochloride
- EPSP/C
- excitatory postsynaptic potential/current
- PBS
- phosphate-buffered saline
- Received May 23, 1997.
- Accepted September 16, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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