Biography:

In the past Benjamin Kest has collaborated on articles with Anthony L. Vaccarino and Karen L. Kepler. One of their most recent publications is Short communicationThe specific N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 blocks U-50,488, but not morphine antinociception☆. Which was published in journal Brain Research.

More information about Benjamin Kest research including statistics on their citations can be found on their Copernicus Academic profile page.

Benjamin Kest's Articles: (20)

Short communicationThe specific N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 blocks U-50,488, but not morphine antinociception☆

AbstractThe effect of the specific NMDA receptor antagonist MK-801 on antinociception produced by the κ opiate receptor agonist U-50,488 and the μ receptor agonist morphine was assessed using the tail-flick test in rats. MK-801 (0.05 and 0.1 mg/kg) antagonized antinociception induced by all three doses of U-50,488 (7.5, 15 and 30 mg/kg), and potentiated antinocicepgion induced by the lower (1 mg/kg) but not higher (5 mg/kg) dose of morphine. Naloxone at a dose of 1.0 but not 0.1 mg/kg blocked U-50,488 antinociception, indicating that MK-801 affects opiate antinociception. The present results are the first to suggest a critical role for the NMDA receptor in opiate antinociception involving the κ receptor.

Short communicationNMDA receptor antagonists, MK-801 and ACEA-1011, prevent the development of tonic pain following subcutaneous formalin☆

AbstractSubcutaneous injection of formalin produces a biphasic pain response: an early, transient phase followed by a late tonic phase. The present study examined the involvement of the N-methyl-d-aspartic acid (NMDA) receptor in the development of the late pain produced following subcutaneous injection of formalin into the hind paw in mice. Blockade of the NMDA receptor by its non-competitive antagonist, MK-801, prior to formalin injection, but not after, reduced pain during the late phase. Similarly, blockade of the NMDA receptor allosteric site by the novel glycine site antagonist, ACEA-1011, also reduced the pain response in the late phase. These results suggest that the development of the late phase of formalin pain is due to NMDA-mediated activity during the early phase.

Rapid communicationIncreases in opioid-mediated swim antinociception following endopeptidase 24.15 inhibition

AbstractThe duration of action and potency of endogenous opioid peptides are limited by proteolytic enzumes such as endopeptidases 24.11 and 24.15. Whereas endopeptidase 24.11 cleaves enkephalin pentapeptides, endopeptidase 24.15 degrades longer-chained opioids including dynorphin A1–8 and met-enkephalin-Arg6-Gly7-Leu8 (MERGL). Inhibitors of endopeptidase 24.11 and 24.15 both increase basal nociceptive thresholds and respective forms of opioid antinociception. Acute exposure to certain environmental stressors can produce antinociception which is opioid mediated; inhibitors of endopeptidase 24.11 potentiate this effect. The present study evaluated whether central administration of a selective inhibitor of endopeptidase 24.15, N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB) increased antinociception following intermittent cold-water swims (ICWS) in rats. cFP-AAF-pAB (0.25–25 nmol, ICV) dose-dependently increased ICWS antinociception on the tail-flick and jump tests without affecting basal nociceptive thresholds. The opioid mediation of ICWS antinociception was confirmed by significant reductions in this response following naloxone. These data indicate that longer-chained endogenous opioid peptides participate in the antinociception induced by ICWS.

Roles of gender, gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats

AbstractGender and gonadal function have previously been shown to influence the magnitude of analgesia following systemic morphine and opioid and nonopioid forms of swim analgesia with male rats displaying greater analgesia than female rats and gonadectomy reducing analgesic magnitude in both genders. These effects have been presumed to be centrally mediated. The present study evaluated the roles of gender, gonadectomy and estrous phase upon dose-response and time-response functions of analgesia following intracerebroventricular administration of morphine as measured by the tail-flick and jump tests. Sham-operated male rats displayed significantly greater magnitudes of peak and total analgesia following central morphine than sham-operated female rats on both nociceptive measures. This striking effect was reflected both in terms of magnitude and ED50; while male rats displayed near-maximal analgesia at a 5 μg dose of morphine, female rats displayed moderate analgesia at doses as high as 40 μg of morphine. Castration produced small, but significant reductions in the magnitude of central morphine analgesia; the ED50 of morphine analgesia, however, was not changed. Although female rats in either proestrous or estrous displayed significantly greater magnitudes of analgesia than ovariectomized rats or rats in a combined met-/di-estrous phase at some doses, the ED50 of morphine analgesia was not significantly altered as functions of estrous phase or ovariectomy. The interaction of opiate receptors and gonadal steroid receptors is considered as one possible determinant of gender differences observed in the magnitude and potency of central morphine analgesia.

Technical reviewN-methyl-d-aspartate (NMDA) receptors, mu and kappa opioid tolerance, and perspectives on new analgesic drug development

This laboratory perspective renews the pharmagologic approaches that have been used in preclinical animal models to demonstrate the ability of competitive (LY274614) and noncompetitive (MK801 and dextromethorphan) N-methyl-d-aspartate (NMDA) receptor antagonists to attenuate or reverse the development of morphine tolerance. We provide additional data to support previous observations that these NMDA antagonists modulate morphine (mu) opioid tolerance but do not affect U50488H (kappa1) opioid tolerance. A strategy, which utilizes efficacy as an NMDA receptor antagonist and clinical safety, provides the basis for a discussion of the clinical potential of dextromethorphan, ketamine, and felbamate as modulators of opioid tolerance in pain patients or opioid addicts. The potential use of NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors in neuropathic pain is also discussed.

Research reportA comparison of morphine analgesic tolerance in male and female mice

AbstractStudies comparing morphine tolerance in males and females are rare, and all studies to date have utilized the rat. To generalize from findings with rats morphine tolerance was investigated in male and female mice using the tail-withdrawal test. Three and 7 days of systemic morphine injections produced significant but unequal rightward shifts in the morphine dose–response curve such that females displayed greater increases in analgesic ED50 values when compared to males. In a separate experiment, males and females displayed similar reductions in morphine analgesic sensitivity when %MPE (maximum possible effect) and %total (area under the curve) were compared after 3 days of morphine. Differences in initial morphine sensitivity between sexes were not observed in either study. The data demonstrate that, in contrast to rats, female mice undergo greater reductions in morphine analgesia relative to males following chronic morphine, but this sex difference may depend on the method of assessing analgesia. Furthermore, the duration and/or cumulative dose of morphine treatment does not affect the expression of sex differences in morphine tolerance.

Short communicationSex differences in systemic morphine analgesic tolerance following intrathecal morphine injections

AbstractMorphine analgesic potency following systemic administration was assessed in male and female mice undergoing prior and repeated intrathecal morphine injections. Although morphine ED50 values were significantly increased in both sexes relative to their respective saline-injected controls, the magnitude of tolerance was greater in females. Intrathecal injection alone had no effect on morphine analgesia. The data suggest that spinal mechanisms contribute to sex differences in analgesic tolerance following systemic morphine administration.

Research ReportGenetic variance contributes to naltrexone-induced inhibition of sucrose intake in inbred and outbred mouse strains

AbstractThe study of genetic variance in opioid receptor antagonism of sucrose and other forms of sweet intake has been limited to reductions in sweet intake in mice that are opioid receptor-deficient or lacking either pre–pro-enkephalin or beta-endorphin. Marked genetic variance in inbred mouse strains has been observed for sucrose intake across a wide array of concentrations in terms of sensitivity, magnitude, percentages of kilocalories consumed as sucrose and compensatory chow intake. The present study examined potential genetic variance in systemic naltrexone's dose-dependent (0.01–5 mg/kg) and time-dependent (5–120 min) ability to decrease sucrose (10%) intake in eleven inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) mouse strains. A minimum criterion sucrose intake (1 ml) under vehicle treatment, designed to avoid “floor effects” of antagonist treatment was not achieved in three (A/J, AKR/J, CBA/J) inbred mouse strains. Marked genetic variance in naltrexone's ability to inhibit sucrose intake was observed in the remaining strains with the greatest sensitivity observed in the C57BL/10J and C57BL/6J strains, intermediate sensitivity in BALB/cJ, C3H/HeJ, CD-1 and DBA/2J mice, and the least sensitivity in 129P3/J, SWR/J and SJL/J strains with a 7.5–36.5 fold range of greater effects in the ID50 of naltrexone-induced inhibition in C57BL/10J relative to the three less-sensitive strains across the time course. Naltrexone primarily affected the maintenance, rather than the initiation of intake in BALB/cJ, CD-1, C3H/HeJ, DBA/2J and SJL/J mice, but significantly reduced sucrose intake at higher doses across the time course in C57BL/6J, C57BL/10J and 129P3/J mice. Whereas SWR/J mice failed to display any significant reduction in sucrose intake at any time point following any of the naltrexone doses, naltrexone's maximal magnitude of inhibitory effects was small (35–40%) in 129P3/J and SJL/J mice, moderate (∼ 50%) in BALB/cJ, C3H/HeJ, CD-1 and DBA2/J mice, and profound (70–80%) in C57BL/6J and C57BL/10J mice. Indeed, the latter two strains displayed significantly greater percentages of naltrexone-induced inhibition of sucrose intake than virtually all other strains. These data indicate the importance of genetic variability in opioid modulation of sucrose intake.

Research reportDifferences in delta opioid receptor antinociception, binding, and mRNA levels between BALB/c and CXBK mice

AbstractMu and delta opioid receptors have been demonstrated to mediate supraspinal opioid antinociception. Whereas the recombinant inbred CXBK mouse is notably deficient in mu opioid receptor antinociception, binding density, and mRNA (MOR-1) levels, little is known about delta opioid receptor processes in this strain. The present study thus compared CXBK mice and their BALB/c strain progenitors with respect to delta opioid antinociception, whole-brain receptor binding levels, and mRNA (DOR-1) levels. Following intracerebroventricular injections of the selective delta1 and delta2 opioids DPDPE and [d-Ala2]deltorphin II, respectively, CXBK mice displayed relatively lower antinociception on the tail-flick test, resulting in significantly increased ED50 values for both agonists in this strain. Decreased whole-brain specific binding of [3H][d-Ala2]deltorphin II, but not [3H]DPDPE, was also observed in CXBK mice. Solution hybridization with a probe for the DOR-1 revealed increased transcript levels in the caudate-putamen, frontal cortex, and spinal cord of this strain. The present data demonstrate a deficiency in delta1 and delta2 opioid antinociception in CXBK mice concomitant with reductions in whole-brain delta2 receptor binding and regional increases in DOR-1. Whether these observations are causally related remains to be clarified.

Sex differences in opioid analgesia, hyperalgesia, tolerance and withdrawal: Central mechanisms of action and roles of gonadal hormones

AbstractThis article reviews sex differences in opiate analgesic and related processes as part of a Special Issue in Hormones and Behavior. The research findings on sex differences are organized in the following manner: (a) systemic opioid analgesia across mu, delta and kappa opioid receptor subtypes and drug efficacy at their respective receptors, (b) effects of the activational and organizational roles of gonadal steroid hormones and estrus phase on systemic analgesic responses, (c) sex differences in spinal opioid analgesia, (d) sex differences in supraspinal opioid analgesia and gonadal hormone effects, (e) the contribution of genetic variance to analgesic sex differences, (f) sex differences in opioid-induced hyperalgesia, (g) sex differences in tolerance and withdrawal-dependence effects, and (h) implications for clinical therapies.

Genetic variance contributes to ingestive processes: A survey of 2-deoxy-d-glucose-induced feeding in eleven inbred mouse strains

AbstractThe feeding response following administration of the anti-metabolic glucose analogue, 2-deoxy-d-glucose (2DG), is conceptualized as an experimental model of glucoprivation, which may contribute to the understanding of inter-individual differences in glucose and carbohydrate intake and, ultimately, obesity. Although variation in the intake of several nutrients as well as food and water are known to be associated with genetic variation, it is not known whether 2DG-induced feeding is similarly genotype dependent. The present study therefore examined 2DG-induced feeding in mice of 11 inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL6/J, C57BL10/J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) strains across a wide range of previously determined effective 2-DG doses (200, 400, 600, 800 mg/kg) and test times (1–4 h). Orderly dose-dependent increases in 2DG-induced feeding occurred after all four doses in outbred CD-1 and inbred DBA/2J mice, across the three highest doses for BALB/cJ, SJL/J and 129P3/J mice, and across the two highest doses for CBA/J and AKR/J mice. Limited instances of 2DG-induced feeding were noted only at the highest dose in A/J and C3H/HeJ mice, or at a moderate dose in C57BL/6J mice. Further, the full 2DG dose range failed to alter food intake in C57BL/10J mice, and produced significant reductions in food intake in SWR/J mice. Food intake after 2DG doses of 200–600 mg/kg, but not 800 mg/kg, displayed significant cross-correlation, suggesting that large 2DG doses may recruit non-specific effects upon food intake. There was no correlation between food intake in the absence (vehicle baseline) of and presence of 2DG, suggesting that the regulation of glucose intake in non-challenged mice does not predict subsequent responses to glucoprivic challenge. The data demonstrate genotype-dependent variability in this glucoprivic response, and may provide the basis for the subsequent identification of trait-relevant genes.

Genetic variance contributes to ingestive processes: A survey of mercaptoacetate-induced feeding in eleven inbred and one outbred mouse strains

AbstractThe feeding response following administration of the free fatty acid oxidation inhibitor, mercaptoacetate (MA) is conceptualized as an experimental model of lipoprivation, which may contribute to the understanding of inter-individual differences in the modulation of this homeostatic response. Although variation in the intake of food, water and glucoprivation as well as intake of several nutrients is known to be associated with genetic variation, it is not known whether MA-induced feeding is similarly dependent upon genotype. The present study therefore examined MA-induced feeding in mice of 11 inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL6/J, C57BL10/J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) strains across a wide range of previously determined effective MA doses (5, 35, 70, 100 mg/kg) and test times (1–4 h). MA produced significant dose-dependent and strain-dependent increases in food intake with strong responses noted in DBA/2J, outbred CD-1 and AKR/J mice. More limited dose-specific increases in food intake following MA occurred in C3H/HeJ, BALB/cJ, CBA/J, SJL/J, SWR/J and C57BL/6J mice. In contrast, MA failed to significantly increase food intake in A/J, C57BL/10J and 129P/3J mice. MA-induced food intake correlated significantly across strains only following the two highest doses, and intake following only the highest MA dose correlated significantly across strains with intake following only a moderate glucoprivic dose of 2-deoxy-d-glucose. Thus, these inter-strain differences suggest that lipoprivic (e.g., MA intake) and glucoprivic (e.g., 2-deoxy-d-glucose intake) responsivity operate via only partially overlapping genetic mechanisms of action. The demonstration of genotype-dependent variability in this lipoprivic response may provide the basis for the subsequent identification of trait-relevant genes.

Spinal and supraspinal N-methyl-d-aspartate and melanocortin-1 receptors contribute to a qualitative sex difference in morphine-induced hyperalgesia

Highlights•Spinal & supraspinal MK-801 or MSG606 reverses MIH in males & females, respectively.•MSG606 was effective in reversing MIH after progesterone injection in OVX mice.•Spinal and supraspinal NMDARs & MC1Rs underlie a qualitative sex difference in MIH.

Genetic variation in morphine analgesic tolerance: A survey of 11 inbred mouse strains

AbstractThe present study assessed the analgesic potency of morphine in 11 inbred mouse strains before and after chronic morphine treatment. Using the 49 °C tail-withdrawal test, significant strain differences in morphine AD50 estimates derived from cumulative dose–response curves were noted prior to tolerance induction on Day 1. AD50 estimates were reassessed on Day 4, after three daily systemic morphine injections for 3 days using an escalating dose schedule (10, 20, and 40 mg/kg sc). In 9 of 11 strains, morphine potency was significantly reduced from 2-fold to as much as 11-fold. Two strains (129P3 and LP) displayed no evidence whatsoever of tolerance development. Neither initial baseline withdrawal latency nor morphine analgesic sensitivity was significantly correlated with tolerance magnitude. Also observed were strain-dependent alterations (mostly hyperalgesia) in baseline tail-withdrawal latencies as a result of chronic morphine treatment. The magnitude of hyperalgesia and analgesic tolerance was significantly correlated among strains, implicating common genetic substrates and supporting their proposed association. The present work demonstrates that the presence and magnitude of morphine analgesic tolerance is genotype-dependent and identifies strains with widely divergent liabilities that should facilitate identification of trait-relevant genes.

A survey of acute and chronic heroin dependence in ten inbred mouse strains: Evidence of genetic correlation with morphine dependence

AbstractHeroin and morphine exposure can cause physical dependence, with symptoms manifesting during their withdrawal. Inter-individual differences in symptom frequency during morphine withdrawal are a common finding that, in rodents, is demonstrably attributable to genotype. However, it is not known whether inter-individual differences characterize heroin withdrawal, and whether such variation can be similarly influenced by genotype. Therefore, we injected mice of ten inbred strains with acute and chronic heroin doses and compared their jumping frequencies, a common index of withdrawal magnitude, during naloxone-precipitated withdrawal. The data revealed significant strain frequency differences (range after acute and chronic heroin injection: 0–104 and 0–142 jumps, respectively) and substantial heritability (h2 = 0.94 to 0.96), indicating that genetic variance is associated with heroin withdrawal. The rank order of strain sensitivity for acute and chronic heroin withdrawal jumping, and for the current heroin and previous morphine strain data, were significantly correlated (r = 0.75–0.94), indicating their genetic and, ultimately, physiological commonality. These data suggest that the genetic liability to heroin dependence remains constant across a period of heroin intake, and that heroin and morphine dependence may benefit from common treatment strategies.

Research reportEffect of supraspinal antisense oligodeoxynucleotide treatment on δ-opioid receptor mRNA levels in mice

AbstractStudies in vivo demonstrate that antisense oligodeoxynucleotide (ODN) treatment specifically reduces the functions mediated by numerous central nervous system (CNS) receptors, including opioid receptors. However, the effects of antisense ODN on the opioid receptor mRNA target, itself are rarely examined. In the present study, the effect of supraspinal antisense ODN administration on δ-opioid receptor (DOR) mRNA levels in selected CNS regions, was investigated in mice. ODN targeting a 20-nucleotide sequence of the DOR mRNA transcript was administered by intracerebroventricular (i.c.v.) injection twice daily for 3 days. First, to confirm that antisense ODN treatment decreases DOR function in this system, antinociception produced by DOR-selective agonist [d-Ala2]deltorphin II was assessed on day 4. A 2-fold reduction in [d-Ala2]deltorphin II potency was revealed in antisense ODN-treated mice compared to mice receiving control treatments. DOR mRNA levels in selected CNS regions which either mediate antinociception; medial thalamus (MThal), periaqueductal gray (PAG), frontal cortex (FCtx) and spinal cord (SpC) or exhibit relatively high levels of DOR mRNA; nucleus accumbens (Acb) and caudate-putamen (CPu) were then quantitated by solution hybridization. Levels of DOR mRNA in antisense ODN-treated mice were not different from levels in mice treated with saline vehicle, which ranged from 0.07 pg/μg total RNA in MThal and PAG to 0.26 pg/μg total RNA in CPu. These results are both consistent with previous reports that antisense oligodeoxynucleotide (ODN) treatment down-regulates DOR protein in vivo and indicate that this down-regulation is not associated with altered DOR mRNA levels.

Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice

AbstractAlthough μ-receptor opioids are clinically important analgesics, they can also paradoxically cause hyperalgesia independently of opioid receptor activity, presumably via the action of neuroexcitatory glucoronide metabolites. However, it is unknown whether the commonly used μ-receptor opioid analgesic fentanyl, which is not subject to glucuronidation, can also induce hyperalgesia independently of opioid receptor activity. Thus, here we examined whether fentanyl increases nociception on the tail-withdrawal test in CD-1 mice concurrently treated with the opioid receptor antagonist naltrexone or in opioid receptor triple knock-out mice lacking μ, δ, and κ opioid receptors. For both groups, an acute fentanyl bolus dose (0.25 mg/kg, s.c.) and continuous fentanyl infusion (cumulative daily dose: 10 mg/kg) did not cause analgesia at any time. Instead, fentanyl significantly decreased withdrawal latencies relative to pre-drug values for the next 15–60 min and for six days, respectively. MK-801 blocked and reversed hyperalgesia caused by the acute injection and continuous infusion of fentanyl, respectively, in naltrexone-treated CD-1 mice, indicating the contribution of NMDA receptors to fentanyl hyperalgesia. These data show that the synthetic opioid fentanyl causes hyperalgesia independently of prior or concurrent opioid receptor activity or analgesia. Since the biotransformation of fentanyl does not yield any known pronociceptive metabolites, these data challenge assumptions regarding the role of neuroexcitatory metabolites in opioid-induced hyperalgesia.

Acute morphine dependence in mice selectively-bred for high and low analgesia

AbstractAcute morphine dependence was compared in mice selectively-bred for high (HA) and low (LA) swim stress-induced analgesia and high (HAR) and low (LAR) levorphanol analgesia by counting the number of naloxone-precipitated jumps. Whereas LAR mice displayed greater acute morphine dependence than HAR mice, HA and LA mice did not differ. No genotypic differences were observed in non-dependent mice, discounting possible differences in basal naloxone sensitivity and/or opioid peptide levels. Thus, the two selection projects, while both producing lines exhibiting highly divergent sensitivity to morphine analgesia, have not had analogous effects on all opioid measures, supporting the notion of independent genetic mediation of opioid analgesia and dependence. Further, these data suggest that analgesic sensitivity may not predict sensitivity to morphine dependence.

Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies

AbstractAlthough a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in μ and mixed μ/κ opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. Across the 25 clinical studies on μ-opioids there was no significant sex-analgesia association. Restricting the analysis to patient-controlled analgesia (PCA) studies (irrespective of the opioid) yielded greater analgesia in women (n = 15, effect size 0.22, 95% c.i. 0.02–0.42, P = 0.028). Further restricting the analysis to PCA morphine studies yielded an even greater effect in women (n = 11, effect size = 0.36, 95% c.i. 0.17–0.56, P = 0.003). Meta-regression indicated that the longer the duration of PCA, the difference in effect between the sexes further increased. Across experimental pain studies on μ-opioids women had greater antinociception from opioids (n = 11, effect size = 0.35; 95% c.i. 0.01–0.69, P = 0.047), which was predominantly due to 6 morphine studies. Female patients had greater μ/κ opioid analgesia (n = 7, effect size 0.84; 95% c.i. 0.25–1.43, P = 0.005), but no sex-analgesia association was present in experimental studies (n = 7). Sex differences exist in morphine-induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non-morphine μ and mixed μ/κ-opioids are less convincing and require further study.

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