Strain differences in the magnitude of swimming-induced analgesia in mice correlate with brain opiate receptor concentration

doi:10.1016/0006-8993(88)90984-5

Brain Research

Volume 447, Issue 1, 26 April 1988, Pages 188-190

https://doi.org/10.1016/0006-8993(88)90984-5 Get rights and content

Abstract

Swimming-induced analgesia was studied in 4 strains of mice differing in central opiate receptor density: C57BL/6By (C57). BALB/cBy (BALB/c). CXBK and CXBH. The degree of ‘swim analgesia’ significantly differed among strains in the order CXBH > BALB/c = C57 > CXBK. This order positively correlates with known differences in opiate receptor density in these strains. Naloxone reversed the analgesic effect of swimming in CXBH, C57 and BALB/c, but was ineffective in opiate receptor-deficient CXBK mice. These results suggest that genetic differences in central opiate receptor density influence the analgesic response to stressful stimuli.

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Cited by (33)

Reduced supraspinal nociceptive responses and distinct gene expression profile in CXBH recombinant inbred mice
2013, Journal of Pain
CXBH mice, known as an “opioid receptor-rich” strain, are a recombinant inbred mouse strain established by crossing the C57BL/6By and BALB/cBy strains. In the present study, we investigated nociceptive and antinociceptive sensitivity in CXBH mice and elucidated the underlying molecular mechanisms. CXBH mice exhibited slightly higher morphine-induced antinociception compared with C57BL/6J and BALB/cBy mice in the hot-plate test but not tail-flick test. CXBH mice exhibited a marked reduction of nociceptive sensitivity, regardless of the type of nociceptive stimulus, with the exception of tail stimulation. Changes in gene expression that corresponded to reduced nociceptive sensitivity in the brains of CXBH mice were observed in 62 transcripts, including pain- and analgesia-related transcripts, in a whole-genome expression assay. The total mRNA expression of opioid receptors was higher in CXBH mice than in C57BL/6J and BALB/cBy mice. However, the expression levels of MOR-1 mRNA, a major transcript of the μ opioid receptor gene, were not different among the C57BL/6J, BALB/cBy, and CXBH strains. In conclusion, supraspinal nociceptive responses were reduced in the CXBH mouse strain, and the expression levels of transcripts were altered in the brain of this strain.
This article presents the nociceptive and antinociceptive properties of CXBH recombinant inbred mice and gene expression differences that may underlie nociceptive tolerance in the strain. The CXBH mouse strain may be a useful animal model to investigate the molecular basis of individual differences in supraspinal pain sensitivity.
Stress-induced analgesia in μ-opioid receptor knockout mice reveals normal function of the δ-opioid receptor system
2000, Brain Research
Citation Excerpt :
The endogenous release of opioid ligands is well studied and can be produced using inescapable shock [5,8], social-conflict [26], or forced swim stresses [7,19,32]. Opioid induced analgesia following forced swim is dependent upon the length of swim [32], parameters of swim (i.e. continuous or intermittent) [7], strain and sex of animal [2,15,16,18,20,21], and water temperature [24]. Although the exact contributions of μ- and δ-receptors in mediating stress-induced analgesias (SIA) remains elusive, both the μ- and δ-receptor subtypes have been implicated in opioid-mediated SIA following forced swim [13,35].
Stress-induced analgesia (SIA) was examined in wildtype and μ-opioid receptor knockout mice. We used thermal paw withdrawal (TPW) latency following a continuous 3-min swim in 20°C water, and found a significant increase in TPW latency in both wild-type and knockout mice. Pre-treatment prior to the swim with naltrindole, a selective δ-opioid receptor antagonist, blocked the increase in TPW latency in knockout mice. These results demonstrate an intact δ-receptor-mediated function of a physiologically-released endogenous agonist in the μ-opioid receptor knockout mouse. The present findings are in contrast with previous reports that analgesia induced by exogenous delta agonists is reduced in the knockout mice.
Unique behavioural phenotypes of recombinant-inbred CXBK mice: Partial deficiency of sensitivity to μ- and κ-agonists
1999, Neuroscience Research
Recombinant-inbred CXBK mice have been used for various studies as putative μ-opioid-receptor deficient mice. However, CXBK mice have never been compared with gene-targeting mice lacking the μ-opioid receptor (μKO) and the κ-opioid receptor (κKO). Here we report that CXBK mice show distinct behavioural phenotype in opioid-induced analgesia and sedation. Intraperitoneal (i.p.) administration of morphine (3 and 10 mg kg⁻¹) induced significantly lower levels of analgesia in CXBK mice than in the control C57BL/6 mice, while higher doses of morphine (30 and 100 mg kg⁻¹) induced marked analgesia in CXBK mice. CXBK mice also showed lower analgesia and sedation levels than did C57 mice after i.p. administration of U-50488 (10 and 30 mg kg⁻¹). The partial deficiency of sensitivity to morphine and U-50488 of CXBK mice is in sharp contrast to the complete lack of sensitivity to morphine and U-50488 in μKO and κKO mice, respectively. Furthermore, CXBK mice showed a lower threshold for nociceptive stimuli when they were not given an opioid, suggesting that CXBK mice could have alterations in the genes related to the nociceptive threshold. These unique behavioural phenotypes of CXBK mice suggest unique genetic alterations in CXBK mice.
Analgesia in selectively bred mice exposed to cold in helium/oxygen atmosphere
1999, Physiology and Behavior
In order to evaluate the stressing role of swim hypothermia in producing swim stress-induced analgesia (SSIA), we examined whether a mere decrease in the animals’ core temperature without swimming would be sufficient to elicit analgesia. The subjects were Swiss–Webster mice selectively bred for 37 and 40 generations for divergent magnitudes of SSIA. High (HA) and low analgesia (LA) mice were exposed for 15 min to temperatures in the range between −5 and +20°C in 79% He/21% O₂ (Heliox) atmosphere. The Heliox exposure produced ambient temperature-dependent hypothermia and analgesia, as assessed with a hot-plate test (56°C). The post-Heliox analgesia was of much higher magnitude in HA than in LA mice. The steeper slope of regression of the magnitude of analgesia upon hypothermia in HA mice indicates that these mice are far more sensitive to the analgesic effect of hypothermia than LA mice. Naltrexone HCl (10 mg/kg i.p.) attenuated analgesia in ambient temperature-dependent manner in HA, but not in LA mice. In view of the apparent similarity of Heliox-induced analgesia and SSIA we suggest that hypothermia is a powerful component of swim stress to induce SSIA in the mouse.
The effect of genotype on sensitivity to inflammatory nociception: Characterization of resistant (A/J) and sensitive (C57BL/6J) inbred mouse strains
1998, Pain
The important role of genetic factors in the mediation of sensitivity to pain and pain inhibition is being increasingly appreciated. In an attempt to systematically study the genotypic influences on inflammatory nociception, we conducted a survey of the nociceptive responsivity of three common outbred mouse strains and 11 inbred mouse strains on the formalin test. The formalin test is known to display a biphasic temporal pattern of behavioral and electrophysiological activity, defined by an acute/early phase and a tonic/late phase. Nociceptive sensitivity (licking/biting of the affected area) to a subcutaneous injection of 5% formalin (25 μl volume) into the plantar surface of the right hindpaw displayed moderate heritability in both phases (0.38 and 0.46, respectively). One strain, A/J, was identified as extremely resistant to formalin nociception, displaying total licking in the acute and tonic phases that was 60% and 87% lower, respectively, than the grand mean of all strains. A subsequent series of experiments were performed to characterize the difference between A/J and C57BL/6J mice. The findings establish this inbred strain comparison as a useful genetic model of nociceptive sensitivity.
Genetic variance in nociception and its relationship to the potency of morphine-induced analgesia in thermal and chemical tests
1998, Pain
The perceived intensity of a painful stimulus is determined in part by the stimulus intensity and environmental conditions. The purpose of this study was to determine the influence of genetic factors in nociception and its contribution to the potency of morphine to produce antinociception. Eight inbred strains of mice were tested across a range of stimulus intensities in thermal (hot plate) and chemical irritant (acetic acid) nociceptive tests. Stimulus intensities in the thermal test included hot plate temperatures of 51, 53, 55, 57 and 59°C. Stimulus intensities in the chemical irritant test included acetic acid concentrations of 0.1, 0.3 and 0.6%. Linear interpolation of stimulus-effect curves revealed large genotype-dependent differences in the effective temperature resulting in a 10 s latency on the hot-plate (ET₁₀″) and the acetic acid concentration resulting in the same number of writhes as determined by the area under the curve (AUC₅₀). There was no genetic correlation between sensitivity to thermal versus chemical stimuli. Morphine dose response curves were then determined at a fixed stimulus intensity in each test (55°C and 0.6% acetic acid) to determine analgesic ED₅₀ doses for each inbred strain. A significant effect of genotype on relative sensitivity to morphine-induced analgesia in both the thermal and chemical irritant tests was found, however there was no genetic correlation between the potency of morphine in each test. There was an inverse genetic correlation between sensitivity to thermal and chemical stimuli and morphine ED₅₀ values in each respective test. In both tests, strains less sensitive to the nociceptive stimuli were more sensitive to the antinociceptive effects of morphine. Confirmation studies in a separate genetic population confirmed the inverse relationship between hot-plate sensitivity and antinoceptive potency. In summary, this study demonstrated (i) a large degree of genetically-determined variability in sensitivity to painful stimuli, (ii) sensitivity to thermal stimuli (hot-plate) is genetically unrelated to sensitivity to chemical (acetic acid) stimuli, (iii) the mechanism by which morphine produces its antinociceptive effects against thermal stimuli is largely genetically independent of the mechanism by which morphine produces its antinociceptive effects against chemical stimuli, and (iv) inherent differences in sensitivity to painful stimuli may be responsible, in part, for individual differences in the potency of morphine's antinociceptive effects.

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^☆: This study was supported by NIH Grant NS-07628 and by a gift from the David H. Murdock Foundation for Advanced Brain Studies.

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Short communicationStrain differences in the magnitude of swimming-induced analgesia in mice correlate with brain opiate receptor concentration☆

Abstract

Life Sci.

Brain Research

Brain Research

Pain

Brain Research

Brain Research

Brain Research

Life Sci.

Short communication
Strain differences in the magnitude of swimming-induced analgesia in mice correlate with brain opiate receptor concentration☆