Genetic dissociation of multiple morphine effects among C57BL/6J, DBA/2J and C3H/HeJ inbred mouse strains

doi:10.1016/0031-9384(89)90324-7

Physiology & Behavior

Volume 46, Issue 1, July 1989, Pages 69-74

https://doi.org/10.1016/0031-9384(89)90324-7 Get rights and content

Abstract

The pattern of sensitivity of mice from three inbred strains were compared on measures of morphine-induced analgesia (hot plate), locomotor activity, hypothermia, Straub tail (muscular rigidity), antidiuresis and constipation. The DBA/2J strain emerged as the most sensitive strain for analgesia, retention of a water load (antidiuresis) and hypothermia. In addition, the DBA/2J mice had lower concentrations of morphine in the brain 30 min after injection and had the lowest K_d and the highest B_max for naloxone as measured by in vitro receptor binding. In contrast, mice of the C57BL/6J strain were most sensitive when locomotor activity, Straub tail and constipation were measured. The C3H/HeJ mice were generally intermediate in their sensitivity to morphine. The observed strain differences indicate a rather high degree of genetic control for most of the effects studied, however, the low consistency of rank order among the three strains across these measures suggests that the genetically determined mechanisms are largely different between these measures of morphine sensitivity.

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Cited by (67)

Do initial responses to drugs predict future use or abuse?
2012, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
The question of the relationship between initial sensitivity and self-administration of opiates has received relatively little attention in nonhuman studies. C57BL/6J inbred strain mice exhibit a larger initial stimulant response to morphine than do DBA/2J mice (Belknap et al., 1989), and DBA/2J mice exhibit a locomotor depressant response to morphine early after administration (Phillips et al., 1994). Consistent with the idea that stimulation is related to reward, morphine supports intravenous self-administration in C57BL/6J, but not DBA/2J mice (Elmer et al., 2010).
Individuals vary in their initial reactions to drugs of abuse in ways that may contribute to the likelihood of subsequent drug use. In humans, most drugs of abuse produce positive subjective states such as euphoria and feelings of well-being, which may facilitate repeated use. In nonhumans, many drugs initially increase locomotor activity and produce discriminative stimulus effects, both of which have been considered to be models of human stimulant and subjective states. Both humans and nonhumans vary in their sensitivity to early acute drug effects in ways that may predict future use or self-administration, and some of these variations appear to be genetic in origin. However, it is not known exactly how the initial responses to drugs in either humans or nonhumans relate to subsequent use or abuse. In humans, positive effects of drugs facilitate continued use of a drug while negative effects discourage use, and in nonhumans, greater genetic risk for drug intake is predicted by reduced sensitivity to drug aversive effects; but whether these initial responses affect escalation of drug use, and the development of dependence is currently unknown. Although early use of a drug is a necessary step in the progression to abuse and dependence, other variables may be of greater importance in the transition from use to abuse. Alternatively, the same variables that predict initial acute drug effects and early use may significantly contribute to continued use, escalation and dependence. Here we review the existing evidence for relations between initial direct drug effects, early use, and continued use. Ultimately, these relations can only be determined from systematic longitudinal studies with comprehensive assessments from early drug responses to progression of problem drug use. In parallel, additional investigation of initial responses in animal models as predictors of drug use will shed light on the underlying mechanisms.
Regional mRNA expression of the endogenous opioid and dopaminergic systems in brains of C57BL/6J and 129P3/J mice: Strain and heroin effects
2011, Pharmacology Biochemistry and Behavior
Citation Excerpt :
There is a large body of data demonstrating considerable individual differences in the vulnerability to develop addictive disease. One way to study these individual, and perhaps genetic, roots of vulnerability is to examine inbred strains of animals which are known to differ in their response to drugs of abuse (e.g. Belknap et al., 1989; Kosten et al., 1994). Numerous neurochemical and drug-induced behavioral differences have been described in C57BL/6J and DBA2 strains of mice (e.g. Castellano et al., 1976; Crabbe et al., 1980; De Waele et al., 1992; Jamensky and Gianoulakis, 1997; Phillips et al., 1994).
We have previously shown strain and dose differences in heroin-induced behavior, reward and regional expression of somatostatin receptor mRNAs in C57BL/6J and 129P3/J mice. Using Real Time PCR we examined the effects of five doses of heroin on the levels of the transcripts of endogenous opioid peptides and their receptors and dopaminergic receptors in the mesocorticolimbic and nigrostriatal pathways in these same mice. Compared to C57BL/6J animals, 129P3/J mice had higher mRNA levels of Oprk1 in the nucleus accumbens and of Oprd1 in the nucleus accumbens and a region containing both the substantia nigra and ventral tegmental area (SN/VTA). In the cortex of 129P3/J mice, lower levels of both Oprk1 and Oprd1 mRNAs were observed. Pdyn mRNA was also lower in the caudate putamen of 129P3/J mice. Strain differences were not found in the levels of Oprm1, Penk or Pomc mRNAs in any region examined. Within strains, complex patterns of heroin dose-dependent changes in the levels of Oprm1, Oprk1 and Oprd1 mRNAs were observed in the SN/VTA. Additionally, Oprd1 mRNA was dose-dependently elevated in the hypothalamus. Also in the hypothalamus, we found higher levels of Drd1a mRNA in C57BL/6J mice than in 129P3/J animals and higher levels of DAT (Slc6a3) mRNA in the caudate putamen of C57BL/6J animals than in 129P3/J counterparts. Heroin had dose-related effects on Drd1a mRNA in the hypothalamus and on Drd2 mRNA in the caudate putamen.
Drug response profiles to experimental pain are opioid and pain modality specific
2011, Journal of Pain
Citation Excerpt :
That the clusters identified in the current study did not differ according to baseline sensitivity could indicate that opioid responsiveness is relatively unrelated to a person’s inherent level of pain sensitivity. Preclinical findings have demonstrated an inverse association between basal nociceptive sensitivity and analgesic efficacy2,12,30; therefore, one might have hypothesized greater baseline pain responses would be associated with reduced opioid analgesia in this population. However, our findings indicate a relative lack of correlation between pain sensitivity and opioid efficacy to particular painful stimuli in healthy individuals.
Given our limited ability to predict analgesic efficacy, further research is needed to understand factors influencing analgesic response patterns. The aim of this study was to better understand the relationship between morphine and butorphanol analgesic efficacy tested against multiple pain modalities within the same individuals. Participants included healthy men (n = 72) and women (n = 67) who underwent thermal, pressure, and ischemic experimental pain testing before and after the double-blind administration of morphine and butorphanol during separate testing sessions. Factor analysis revealed 6 factors with analgesic effects grouped primarily by pain modality and specific to either morphine or butorphanol. Hierarchical cluster analysis of individual factor scores led to 4 distinct drug response profiles. Three groups displayed exceptional analgesic efficacy produced by 1 type of opioid on 1 pain stimulus modality, whereas the fourth drug response profile was characterized by average analgesic efficacy across all pain modalities for both opioids. These findings suggest that opioids with varying efficacy at the μ and κ receptors produce independent effects on unique pain mechanisms and that individual responsiveness for some is dependent on pain mechanism and opioid type, although a subset of the population is moderately responsive to opioids regardless of efficacy of receptor binding or predominant pain mechanism being activated.
This investigation provides a foundation for understanding patterns of opioid efficacy in varying types of pain. Our findings suggest that opioid response patterns are more complex than originally thought with about half of individuals exhibiting opioid and pain modality specific analgesic response profiles.
Taste reactivity and its modulation by morphine and methamphetamine in C57BL/6 and DBA/2 mice
2009, Physiology and Behavior
Citation Excerpt :
This is because genuine changes in palatability are hypothesized to be reflected in a change in just one category (positive or aversive), or opposing changes in two categories. Morphine stimulated locomotion in both strains in the current study, particularly in B6 mice, as previously reported [28,29]. We noticed that the overall decreases in taste reactivity scores in all categories were due to decreases in specific behaviors that were likely in conflict with increased locomotion, such as paw licking, grooming and single tongue protrusion [13].
C57BL/6J (B6) and DBA2/J (D2) mice differ markedly in voluntary consumption of tastants and responses to abused drugs. In particular, compared to D2 mice, B6 mice avidly drink ethanol and sucrose solutions, but avoid quinine solutions. In the first study, we compared taste reactivity in B6 and D2 mice to determine the extent to which differences in drinking patterns depend on orosensory processing. Both strains showed concentration-dependent increases in positive reactions to sucrose (0.01 to 1 M). Quinine (0.03 to 3 mM) elicited concentration-dependent aversive reactions in B6 mice, whereas all reactions to quinine were virtually indistinguishable from reactions to water in D2 mice. In contrast, D2 mice reacted with relatively strong aversive responses to ethanol (5 to 30%). In the second study, we evaluated the effect of subcutaneous morphine (1 to 4 mg/kg) and methamphetamine (0.5 to 2 mg/kg) on taste reactivity to sucrose. Morphine generally decreased reactions to sucrose in both strains, suggesting a general motor depressant effect. Methamphetamine shifted sucrose responses towards aversion in both strains; particularly in D2 mice. These results suggest that strain-dependent differences in voluntary ethanol and quinine drinking depend at least partially on differences in orosensory responses. However, differences in voluntary sucrose intake may relate solely to genetic differences in post-ingestive factors. Finally, as has been suggested by previous place conditioning studies, methamphetamine appears to induce a dysphoric state in D2 mice, which may be reflected in fewer positive and more negative taste reactions to sucrose in the current study.
Spontaneous nociceptive behaviour in female mice with Freund's complete adjuvant- and carrageenan-induced monoarthritis
2007, Brain Research
Citation Excerpt :
NMRI mice were found to be significantly more susceptible to adjuvant-induced pain in terms of duration, than BALB/c mice. It has previously been shown that various mouse strains exhibit considerable differences in response to nociceptive stimulation (Elmer et al., 1998; Mogil et al., 1999) and morphine antinociception (Belknap et al., 1989; Elmer et al., 1998). Most of these studies have been performed with thermal or electrical pain stimuli to evoke acute pain (for review, see Mogil et al., 1999).
The development of transgenic techniques has accentuated the need for valid disease models in mice. In the present study, we have in female mice characterized adjuvant-induced monoarthritis, an inflammatory model which is commonly used in rats. Freund's complete adjuvant (FCA), 20 μl, was injected into the left knee joint. Pain was inferred from impairment of gait and stance. Two commonly used mouse strains were compared. Outbred NMRI mice showed significant levels of pain behaviour lasting for at least 7 days after injection of FCA while inbred BALB/c mice showed altered behaviour at 3, but not at 5 days. The effects of three commercially available preparations of FCA were compared in NMRI mice. All adjuvants caused highly reproducible spontaneous pain behaviour at 1–3 days with a reduction at 5 days and no significant pain-related behaviour at 10 days. Intraarticular injection of 2% carrageenan performed for comparison, caused pain-related behaviour for less than 24 h. The adjuvant-induced pain behaviour was dose-dependently reduced by 3–30 μmol/kg morphine and 3–30 μmol/kg diclofenac. In conclusion, adjuvant-induced monoarthritis in mice provides a robust model for pharmacological studies of inflammatory pain, but the choice of mouse strain is important for the outcome.
Individual Differences in Morphine and Butorphanol Analgesia: A Laboratory Pain Study
2011, Pain Medicine
Citation Excerpt :
One explanation for this is that heat pain was not particularly sensitive to the opioids administered, as postdrug changes in heat pain measures were quite modest in magnitude. Another potential consideration is whether race differences in baseline pain sensitivity may have contributed to differences in analgesic effects, as preclinical studies have demonstrated an inverse relationship between basal pain sensitivity and analgesic, antinociceptive response [51–53]. However, this seems unlikely to account for the present findings for several reasons.
Responses to opioid analgesics are highly variable, and the understanding of contributing factors is limited. This laboratory study was designed to examine the contributions of sex and race to inter-individual variability in response to opioids.
A randomized, double-blind, mixed design was implemented in the evaluation of analgesic response to a μ-opioid agonist and mixed agonist–antagonist, using three well-validated experimental pain assays (thermal, pressure, and ischemic).
Participants included a total of 142 healthy subjects (76 men/66 women), 119 non-Hispanic whites and 23 African Americans.
Three sessions of pain testing were completed prior to and following an intravenous administration of morphine (0.08 mg/kg), butorphanol (0.016 mg/kg), and placebo (saline) in counterbalanced order.
A change score was calculated from the difference between the pre-drug and postdrug values. Three separate change scores (morphine, saline, and butorphanol) were computed for each experimental pain variable. Mixed-model analyses of covariance were performed on analgesic change scores.
Significant sex differences emerged for predrug pain measures with minimal differences for race.
Sex differences in opioid analgesia were not demonstrated. However, significant race differences and race X drug interactions emerged for thermal, pressure, and ischemic pain measures. The pattern of results generally indicated that for pressure and ischemic pain, African American subjects showed greater analgesic responses to both medications compared with non-Hispanic whites. For thermal pain threshold, butorphanol but not morphine analgesia was greater for African American vs non-Hispanic whites.
Findings are among the first to demonstrate race differences in a laboratory study of opioid analgesia.

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Genetic dissociation of multiple morphine effects among C57BL/6J, DBA/2J and C3H/HeJ inbred mouse strains

Abstract

Eur. J. Pharmacol.

Brain Res.

J. Biol. Chem.

Effects of L- and D-amino acids on analgesia and locomotor activity of mice: Their interaction with morphine

Brain Res.

Selective breeding for high and low levels of opiate-induced analgesia in mice

Behav. Genet.

Comparison of the effects of morphine on locomotor activity, analgesia and primary and protracted physical dependence in six mouse strains

J. Pharmacol. Exp. Ther.

Heterogeneity and properties of opiate receptors

Genotype and test experience determine responsiveness to morphine

Psychopharmacology

The role of genetics in substance abuse

Pharmacogenetic tools in the study of drug tolerence and dependence

Subst. Alcohol. Actions Misuse

Inbred strains in biomedical research