Disparate spinal and supraspinal opioid antinociceptive responses in β-endorphin-deficient mutant mice
Section snippets
β-Endorphin mutant mice
The gene targeting vector, POMCX*4, and production of β-endorphin null mutant mice are described fully in Rubinstein et al.32 In brief, a point mutation was introduced by site-directed mutagenesis into exon 3 of the POMC gene to generate a premature translational stop codon. The resultant truncated prohormone lacks the carboxyl-terminal 31 amino acids composing β-endorphin, but is expressed at normal levels and correctly processed to adrenocorticotropic hormone (ACTH), melanocyte stimulating
Baseline tail-withdrawal latencies and effect of vehicle injection
Combining data from all experiments, a significant KO>WT difference in baseline 49°C tail-withdrawal latency was observed (3.0±0.1 vs 2.7±0.1 s, respectively; t338=2.65, P<0.005). This small genotypic difference had not been seen previously; the present study, however, provided far greater statistical power owing to the very large number of total subjects. Indeed, the difference was significant in only one individual experiment in the present study (WT vs KO, i.c.v. DAMGO).
Repeated-measure
Discussion
In this study we demonstrate reciprocal alterations in supraspinal and spinal opioid antinociception in null mutant mice lacking β-endorphin. KO mice were found to be more and less sensitive, respectively, than their WT counterparts to antinociception from i.c.v. and i.t. morphine. Although morphine, especially at high doses, can bind to δ- and κ-opioid receptors,36 the phenomenon described presently was shown to be selectively related to μ antinociception since parallel results were obtained
Conclusions
Although the antinociceptive actions of systemically administered morphine were unaltered in mice lacking β-endorphin, opposing effects were seen in the mutant mice when morphine was specifically injected into the supraspinal or spinal compartments. Relative to WT mice of the same C57BL/6 congenic background, KO mice displayed increased antinociceptive sensitivity to i.c.v. morphine, but decreased sensitivity to i.t. morphine. Both phenomena are apparently related to the μ-opioid receptor,
Acknowledgements
The authors thank C. Fjeld, C. MacPherson and S. Lapostolle for maintaining and genotyping the mutant mouse colony and Y. Fang for invaluable advice on receptor autoradiography. This work was supported by R01 DE12735 and R29 DA11394 (J.S.M.), start-up funding from Furman University (J.E.G.), F32 DA05841 (M.D.H.), VA Merit Review No. 350 (J.K.B.) and P01 DK55819 (M.J.L.).
References (47)
- et al.
Region-specific up-regulation of opioid receptor binding in enkephalin knockout mice
Molec. Brain Res.
(1999) - et al.
Strategies for studying opioid peptide regulation at the gene, message and protein levels
Peptides
(1984) Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype?
Trends Neurosci.
(1996)- et al.
The orphan opioid receptor and its endogenous ligand—nociceptin/orphanin FQ
Trends pharmac. Sci.
(1997) - et al.
Intrathecal morphine in mice: a new technique
Eur. J. Pharmac.
(1980) - et al.
Quantitative autoradiographic mapping of μ-, δ- and κ-opioid receptors in knockout mice lacking the μ-opioid receptor gene
Brain Res.
(1997) - et al.
Intracerebroventricular injections in mice: some methodological refinements
J. pharmac. Meth.
(1986) Multiple opioid systems and pain
Pain
(1986)- et al.
Transgenic studies of pain
Pain
(1998) - et al.
Orphanin FQ is a functional anti-opioid peptide
Neuroscience
(1996)
Mu-opiate receptor binding is up-regulated in mice selectively bred for high stress-induced analgesia
Brain Res.
Nociceptive and morphine antinociceptive sensitivity of 129 and C57BL/6 inbred mouse strains: implications for transgenic knock-out studies
Eur. J. Pain
Heritability of nociception. I. Responses of eleven inbred mouse strains on twelve measures of nociception
Pain
Evidence for the existence of the β-endorphin-sensitive “ε-opioid receptor” in the brain: the mechanisms of ε-mediated antinociception
Jpn. J. Pharmac.
Characterization of supraspinal antinociceptive actions of opioid delta agonists in the rat
Pain
Different receptor subtypes mediate spinal and supraspinal analgesia in mice
Eur. J. Pharmac.
Tolerance to morphine analgesia: decreased multiplicative interaction between spinal and supraspinal sites
Brain Res.
Quantitative autoradiography of μ-,δ- and κ1 opioid receptors in κ-opioid receptor knockout mice
Brain Res.
Enkephalin antinociception in mice is mediated by δ1- and δ2-opioid receptors in the brain and spinal cord, respectively
Eur. J. Pharmac.
Spinal opiate analgesia: characteristics and principles of action
Pain
Narcotic analgesics: CNS sites and mechanisms of action as revealed by intracerebral injection techniques
Pain
Nociceptin/orphanin FQ: role in nociceptive information processing
Prog. Neurobiol.
Nociceptive stimulus induces release of endogenous β-endorphin in the rat brain
Neuroscience
Cited by (20)
β-endorphin regulates alcohol consumption induced by exercise restriction in female mice
2016, AlcoholCitation Excerpt :These data, adding to a body of both clinical and basic evidence (cf. del Arbol et al., 1995; Thiagarajan, Mefford, & Eskay, 1989), support the idea that β-endorphin modulates endocrine and behavioral components of the stress response and may contribute to an increased susceptibility for heavy drinking. Moreover, the use of low-endorphin heterozygous mice (βE-HT) in our study enables a more nuanced analysis for the role of this peptide beyond what has been shown in earlier studies only comparing knockouts and wild-types (Mogil et al., 2000; Racz et al., 2008) and may better model the human condition. β-endorphin produces its effects by acting on μ, δ, and κ opioid receptors, binding preferentially to the μ receptor (Hallberg & Nyberg, 2003).
Nicotine anxiogenic and rewarding effects are decreased in mice lacking β-endorphin
2009, NeuropharmacologyCitation Excerpt :The change in the spontaneous locomotor responses of mice lacking β-endorphin further emphasizes the role played by β-endorphin in the control of locomotion. The enhancement of the spontaneous nociceptive threshold of β-endorphin KO mice was mainly revealed in the tail-immersion test, in agreement with previous results (Mogil et al., 2000). This enhanced nociceptive threshold might reflect a compensatory regulation of other neurobiological mechanisms involved in pain control.
Exploring the opioid system by gene knockout
2002, Progress in NeurobiologyCitation Excerpt :Finally, morphine analgesia, hyperlocomotion, reward and withdrawal were unchanged in the Pdyn mutant (Zimmer et al., 2001), indicating that major morphine effects do not require the presence of endogenous prodynorphin peptides. Similarly systemic morphine analgesia was unchanged in the absence of βend (Rubinstein et al., 1996), while subtle modifications were noted when morphine was administered intracerebroventricular (i.c.v.) or intrathecal (i.t.) (Mogil et al., 2000). The analysis of in vivo responses of opioid receptor-deficient mice to kappa agonists has provided results consistent with the previous pharmacology (Table 4).
The Role of Beta-Endorphin in Cocaine-Induced Conditioned Place Preference, Its Extinction, and Reinstatement in Male and Female Mice
2021, Frontiers in Behavioral NeuroscienceRegulation of Opioid Receptors by Their Endogenous Opioid Peptides
2021, Cellular and Molecular NeurobiologyFive decades of research on opioid peptides: Current knowledge and unanswered questions
2020, Molecular Pharmacology