Pertussis toxin differentially reduces the efficay of opioids to produce supraspinal analgesia in the mouse

doi:10.1016/0014-2999(88)90732-7

European Journal of Pharmacology

Volume 152, Issue 3, 2 August 1988, Pages 357-361

https://doi.org/10.1016/0014-2999(88)90732-7 Get rights and content

Abstract

The i.c.v. administration of 0.5 μg pertussis toxin to mice led to a non-competitive reduction (approximately 60 to 70%) of the supraspinal analgesia evoked by i.c.v. injection of ED₉₀ doses of [D-Ala²,N-MePhe⁴,Gly-ol⁵]enkephalin, [D-Ala²,N-MePhe⁴,Met-(O)⁵-ol]enkephalin, [D-Ala²,Met⁵]enkephalinamide, [D-Ala²,D-Leu⁵]enkephalin or [D-Pen²,D-Pen⁵]enkephalin, whereas the analgesic effect of ED₉₀ doses of morphine, etorphine, β--asomorphin-(1–4) amide or human β-endorphin was reduced to a lesser extent (about 20 to 30%). The co-administration of any of the opioids from the first group together with morphine resulted in antagonism of the effect elicited by the alkaloid. It is suggested that pertussis toxin treatment reduces differentially the efficacy displayed by various opioids when acting via μ receptors to produce supraspinal analgesia.

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Distinguishing subgroups among μ-opioid receptor agonists using Na+,K+-ATPase as an effector mechanism
2016, European Journal of Pharmacology
Citation Excerpt :
There are several facts that support this idea. Firstly, pertussis toxin and N-ethylmaleimide, two drugs that inactivate Gi/Go-proteins, differentially reduce the antinociception induced by several μ-opioid receptor agonists (Sánchez-Blázquez and Garzón, 1988; Sánchez-Blázquez et al., 1989). Secondly, a Gi2α antisense oligodeoxyribonucleotide antagonises morphine- but not sufentanil-induced antinociception (Raffa et al., 1994).
We evaluated the effects of intracerebroventricular administration of ouabain on the antinociception induced by five μ-opioid receptor agonists in a tail flick test on female CD-1 mice and the effects of these μ-opioid receptor agonists on mice forebrain synaptosomal ouabain-sensitive Na⁺,K⁺-ATPase activity. The subcutaneous administration of the μ-opioid receptor agonists tested produced a dose-dependent antinociceptive effect. The antinociception induced by morphine (1–32 mg/kg), levorphanol (0.4–6.4 mg/kg), and buprenorphine (0.02–0.64 mg/kg) was antagonised in a dose-dependent manner by ouabain (0.001–10 ng, i.c.v.), whilst the antinociception produced by fentanyl (0.02–0.16 mg/kg) and methadone (2–10 mg/kg) was not influenced significantly by ouabain (1–100 ng, i.c.v.). Incubation in vitro of forebrain synaptosomes with morphine (10⁻⁹–10⁻⁴ M), levorphanol (10⁻¹⁰–10⁻⁴ M), buprenorphine (10⁻¹⁰–10⁻⁵ M), or fentanyl (10⁻¹⁰–10⁻⁵ M) stimulated significantly ouabain-sensitive Na⁺,K⁺-ATPase activity in a concentration-dependent way. The order of efficacy (using the E_max as a measure of intrinsic efficacy) was: morphine (29.83±0.56%)>levorphanol (18.61±1.26%)>buprenorphine (14.91±0.74%)>fentanyl (10.10±1.73%). On the other hand, methadone (10⁻¹⁰–10⁻⁵ M) did not significantly modify the ouabain-sensitive Na⁺,K⁺-ATPase activity (E_max=5.11±0.92%). These results suggest that Na⁺,K⁺-ATPase activity is involved in the antinociceptive effects of morphine, levorphanol and buprenorphine, but not in that produced by fentanyl and methadone. Thus, we can conclude that at least two subgroups can be distinguished among the μ-opioid receptor agonists taking into consideration the role of Na⁺,K⁺-ATPase in their antinociceptive effects.
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Nonetheless, acute effects may have been due to their action in the CNS. Nociception paradigms such as the current-induced vocalization test (Brantl et al., 1981, 1982; Grecksch et al., 1981; Matthies et al., 1984), the hot plate test (Grecksch et al., 1981), the tail-flick test (Sánchez-Blázquez and Garzón, 1988; Taiwo et al., 1989; Widy-Tyszkiewicz and Czlonkowski, 1989; Zhang et al., 1981), the assessment of the tail withdrawal response to hot water (Chang et al., 1982, 1983), the paw withdrawal test (Taiwo et al., 1989), and the tail compression test (Widy-Tyszkiewicz and Czlonkowski, 1989) were used. Results were largely unanimous; with the exception BCM-3 (Brantl et al., 1982; Chang et al., 1982), all of these peptides produced analgesic effects that were blocked by several opioid antagonists, including naloxone (Brantl et al., 1981), naltrexone (Grecksch et al., 1981), and naloxazone (Zhang et al., 1981), thus suggesting that BCM-induced analgesia was mediated by central μ receptors.
Dohan proposed that an overload of dietary peptides, such as those derived from wheat gluten and milk casein, could be a factor relevant to the development or maintenance of schizophrenia (SZ) symptoms in at least a subset of vulnerable individuals. Rodent behavioral models may offer insight into the plausibility of Dohan's exorphin hypothesis by providing a means to directly study the effects of such peptides. Accordingly, a review of the literature on the behavioral effects of food-derived opioid-like peptides in rodents was undertaken. Studies using a variety of behavioral tests to examine the effects of several classes of food-derived opioid-like peptides were identified and reviewed. Peptides derived from casein (β-casomorphins; BCMs, n = 19), spinach (rubiscolins; RCs, n = 4), and soy (soymorphins; SMs, n = 1) were behaviorally active in various paradigms assessing nociception, spontaneous behavior, and memory. Surprisingly, only a single study evaluating a gluten-derived peptide (gliadorphin-7; GD-7, n = 1) was identified and included in this review. In conclusion, food-derived peptides can affect rodent behavior, but more studies of GDs using diverse behavioral batteries are warranted. Assuming they occur in sufficient quantities during protein digestion and can access central opioid receptors (which entails crossing both the gastrointestinal and blood–brain barriers intact), these peptides may affect human behavior. Although BCMs and GDs may not be directly pathogenic in SZ, documented associations of casein and gluten sensitivity with SZ justify increased patient screening and dietary intervention where necessary.
Buprenorphine
2013, Journal of Pain and Symptom Management
Citation Excerpt :
Studies in volunteers suggest that compared to morphine and other opioids, buprenorphine exerts a more prominent antihyperalgesic than analgesic effect;12,13 however, this is not a consistent finding.14 Animal studies and case reports also suggest that buprenorphine may be of particular benefit in neuropathic pain,2,15 but controlled studies are needed to confirm this.6,16–18 The co-administration of an ultra-low dose of an opioid antagonist potentiated the analgesic effect of buprenorphine (as with other opioids) in healthy volunteers but not in patients.19,20
Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]).
RGS-Rz and RGS9-2 proteins control mu-opioid receptor desensitisation in CNS: The role of activated Gαz subunits
2005, Neuropharmacology
Citation Excerpt :
These observations suggest that delta receptors influence the signalling of mu receptors by allosteric interactions within the heterodimers, and probably by the activation of G proteins and certain RGS proteins as well. Although the great majority of mu opioid agonists studied so far propagate their effects through Gi and Gz proteins (Sánchez-Blázquez and Garzón, 1988; Sánchez-Blázquez et al., 2001), they show differences in their preference for activating either one or the other. After binding to mu receptors, the synthetic opioid peptides [d-Ala2,d-Leu5] encephalin (DADLE) and [d-Ser2,Leu5] encephalin-Thr6 (DSLET) activate Gi2 proteins much better than Gz proteins (Garzón et al., 1994, 1998).
Two consecutive icv administrations of analgesic doses of mu-opioid receptor agonists lead to a profound desensitisation of the latter receptors; a third dose produced less than 20% of the effect obtained with the first administration. Desensitisation was still effective 24 h later. Impairing the activity of Gαz but not Gαi2 subunits prevented tolerance developing after the administration of three consecutive doses of morphine. Further, the icv injection of Gαi2 subunits potentiated morphine analgesia and abolished acute tolerance, whereas icv-administered Gαz subunits produced a rapid and robust loss of the response to morphine. The RGSZ1 and RGSZ2 proteins selectively deactivate GαzGTP subunits, and their knockdown increased the effects produced by the first dose of morphine. However, impairing their activity also accelerated tachyphylaxis following successive doses of morphine, and facilitated the development of acute morphine tolerance. In contrast, inhibiting the RGS9-2 proteins, which bind to GαoGTP and GαiGTP but only weakly deactivates them, preserved the effects of consecutive morphine doses and abolished the generation of acute tolerance. Therefore, desensitisation of mu-opioid receptors can be achieved by reducing the responsiveness of post-receptor elements (via the possible action of activated Gαz subunits) and/or by depleting the pool of receptor-regulated G proteins that agonists need to propagate their effects, e.g., through the activity of RGS9-2 proteins.
Role of L-type Ca2+ channels in pertussis toxin induced antagonism of U50,488H analgesia and hypothermia
2002, Brain Research
Citation Excerpt :
Several studies have used PTX pretreatment as a tool to assess the role of G-protein mediated events on the pharmacodynamics of morphine. The pretreatment of PTX has been shown to reduce the analgesic effect of μ-opioid agonists [18,26,33,34,37,40,41,46]. Moreover, PTX pretreatment converts the hypothermia produced by a high dose of morphine into consistent hyperthermia [2].
Previous studies have shown that the κ-opioid effects are sensitive to pertussis toxin (PTX) and affected by Ca²⁺ fluxes. However, the possible involvement of Ca²⁺ channels in PTX-induced inhibition of κ-opioid effects has not been reported. The effect of intracerebroventricular (i.c.v.) treatment of pertussis toxin (1 μg/rat, PTX) or saline on the κ-opioid agonist, U-50,488H (U5H) induced tail-flick analgesia and hypothermia in rats was determined. The effect of nimodipine (NIM), a dihydropyridine (DHP)-sensitive Ca²⁺ channel blocker (CCB), on PTX-induced modulation of U5H effects was examined. The DHP ligand, [³H]PN200–110 binding was also determined in both PTX and saline treated rats to study the possible involvement of L-type Ca²⁺ channels in PTX modulation of κ-opioid agonist effects. The analgesia and change in colonic temperature were determined using tail-flick analgesiometer and telethermometer, respectively. U5H (40 mg/kg, i.p.) produced significant analgesic and hypothermic responses. PTX treatment significantly (P<0.01) antagonized the analgesic and hypothermic effects of U5H. Acute pretreatment of NIM (1 mg/kg, i.p.) 15 min prior significantly (P<0.01) reversed the PTX-induced antagonism of U5H effects. In the binding study, PTX treatment (72 h before) resulted in a significant (P<0.005) upregulation (+45% vs. saline control) of DHP binding (B_max) with no change in affinity (K_d). The results showed significant upregulation of DHP binding in accordance with PTX-induced antagonism of U5H effects and this blockade was reversed by NIM. Thus, present results suggest that U5H-induced analgesia and hypothermia may be mediated through PTX-sensitive transducer G-proteins (G_i/o) coupled to L-type Ca²⁺ channels.
Agonists determine the pattern of G-protein activation in μ-opioid receptor-mediated supraspinal analgesia
2001, Brain Research Bulletin
The opioids heroin, methadone, buprenorphine, and morphine produce supraspinal antinociception in CD-1 mice that is antagonized by Cys², Tyr³, Orn⁵, Pen⁷-amide but not by naltrindole or nor-binaltorphimine. The patterns of GTP-binding regulatory proteins (G-proteins) activation exhibited by these agonists at μ-opioid receptors were characterized. The expression of α-subunits of Gi-protein classes, Gi1, Gi2, Gi3, Go1, Go2 and Gz, and those of the Gq-protein family, Gq and G11, was reduced by administration of antisense oligodeoxynucleotides (ODNs) complementary to sequences in their respective mRNAs. The ODN treatments demonstrated differences in the analgesic profiles of these opioids. Though the knock-down of G_i2α or G_zα subunits diminished the analgesic effets of the four opioids, impairment of G_i3α did not modify the potency of morphine. In mice with reduced G_i1α, G_o1α or G₁₁α levels, antinociception induced by heroin and methadone was diminished, but buprenorphine and morphine showed no change in their effects. Also, antinociception induced by heroin and buprenorphine, but neither morphine nor methadone, required intact G_o2α or G_qα levels. Thus, morphine, heroin, methadone, and buprenorphine showed different patterns of G-protein activation in evoking μ-opioid receptor-mediated supraspinal antinociception. Therefore, after binding identical receptors, each agonist determines the classes of GTP-binding regulatory transducer proteins to be activated.

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European Journal of Pharmacology

Abstract

References (10)

Use of μ and σ opioid peptides of various selectivity gives further evidence of specific involvement of μ opioid receptors in supraspinal analgesia (tail-flick test)

European J. Pharmacol.

Pertussis toxin inhibits antinociception produced by intrathecal injection of morphine, noradrenaline and baclofen

European J. Pharmacol.

Pertussis toxin inhibits the antinociceptive action of morphine in the rat

European J. Pharmacol.

Pertussis toxin abolishes the antinociception mediated by opioid receptors in rat spinal cord

European J. Pharmacol.

Stimulation and inhibition of adenyl cyclases mediated by distinct regulatory proteins

Nature

Cited by (60)

Distinguishing subgroups among μ-opioid receptor agonists using Na<sup>+</sup>,K<sup>+</sup>-ATPase as an effector mechanism

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Buprenorphine

RGS-Rz and RGS9-2 proteins control mu-opioid receptor desensitisation in CNS: The role of activated Gαz subunits

Role of L-type Ca<sup>2+</sup> channels in pertussis toxin induced antagonism of U50,488H analgesia and hypothermia

Agonists determine the pattern of G-protein activation in μ-opioid receptor-mediated supraspinal analgesia

Short communicationPertussis toxin differentially reduces the efficay of opioids to produce supraspinal analgesia in the mouse

Abstract

European J. Pharmacol.

European J. Pharmacol.

European J. Pharmacol.

European J. Pharmacol.

Stimulation and inhibition of adenyl cyclases mediated by distinct regulatory proteins

Nature

Short communication
Pertussis toxin differentially reduces the efficay of opioids to produce supraspinal analgesia in the mouse