Spinal and supraspinal effects of pertussis toxin on opioid analgesia

doi:10.1016/0091-3057(94)90101-5

Pharmacology Biochemistry and Behavior

Volume 49, Issue 3, November 1994, Pages 773-776

https://doi.org/10.1016/0091-3057(94)90101-5 Get rights and content

Abstract

The effects of in vivo pertussis toxin (PTX) treatment on the functional effects of opioid agonists were examined in the mouse. Mice were injected intracerebroventricularly (ICV), or intrathecally (IT), or IT and ICV with PTX, and dose-response studies of the antinociceptive action of systematic (SC) morphine, fentanyl, and etorpine were conducted 10 days later. IT PTX decreased the potency (≈ 4.5-fold) of morphine more than ICV administration (≈ 1.5-fold) whereas the combinationof IT and ICV administration produced an additive effect. When PTX was administered spinally and supraspinally, the potency of morphine, fentanyl, and etorphine was reduced similarly (≈ 5–7-fold), indicating that the effect of PTX does not vary considerably among agonists of different intrinsic efficacies. These studies indicate that in vivo PTX can reduce the potency of opioid agonists with different intrinsic efficacies, and that spinal mechanisms appear to be more sensitive to PTX treatment.

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Cited by (29)

Ultra-low dose naloxone restores the antinocicepitve effect of morphine in PTX-treated rats: Association of IL-10 upregulation in the spinal cord
2012, Life Sciences
Citation Excerpt :
This model has been used as an animal model to study the pathophysiology of neuropathic pain (Womer and Shannon, 2000). Similar phenomenon had been demonstrated in the intrathecal PTX treated animals with reduction of the antinociceptive potency of opioid agonists (Shah et al., 1994). By using the PTX model, Womer et al. (1997) also found that morphine is less effective in treating central and neuropathic pains than treating acute pain (Womer et al., 1997).
Ultra-low dose naloxone has been shown to restore the antinociceptive effect of morphine in pertussis toxin (PTX)-treated rats by suppressing spinal microglia activation and inhibiting inflammatory cytokine expression. This study was further investigated the mechanism by which ultra-low dose naloxone promotes analgesia in pertussis toxin-treated rats.
Male Wistar rats were implanted with an intrathecal (i.t.) catheter and injected either saline or PTX (1 μg). Four days later, rats randomly received either saline, or ultra-low dose naloxone, or recombinant rat interleukin-10 (rrIL-10) (1 μg) injection followed by saline or morphine (10 μg) 30 min later. In some experiments, mouse anti-rat IL-10 antibody (10 μg) was injected intrathecally into PTX injected rats daily on days 4, 5, 6, and 7. On day 7, ultra-low dose naloxone was given 1 h after antibody injection with or without subsequent morphine injection.
PTX injection induced notable thermal hyperalgesia and mechanical allodynia. Injection of ultra-low dose naloxone preserved the antinociceptive effect of morphine in PTX-treated rats and associated an increasing of IL-10 protein expression. Intrathecal injection rrIL-10 alone or in combination with morphine, not only reversed mechanical allodynia but also partially restored the antinociceptive effect of morphine; injection of anti-rat IL-10 antibody attenuated the effect of morphine plus ultra-low dose naloxone on mechanical allodynia and completely inhibited the antinociceptive effect of morphine.
These results indicate that intrathecal ultra-low dose naloxone induces IL-10 expression in spinal neuron and microglia, which suppresses PTX-induced neuroinflammation and restores the antinociceptive effect of morphine.
Ultra-low-dose naloxone enhances the antinociceptive effect of morphine in PTX-treated rats: Regulation on global histone methylation
2012, Acta Anaesthesiologica Taiwanica
Citation Excerpt :
The PTX model had been used to study the pathophysiology of neuropathic pain.12 Certain studies had demonstrated that intrathecal PTX injection could reduce the antinociceptive potency of etorphine, fentanyl,13 and selective μ-agonist PL017.14 Womer et al found that PTX could disrupt the antinociceptive signal transduction of morphine, and therefore reduced morphine's effect in treating central and neuropathic pains than treating acute pain.15
Epigenetic reprogramming may have a possible role in neuropathic pain development; the present study examined the global patterns of lysine histone modification. In this serial study we analyzed the levels of histone 3 lysine 4 monomethylation, histone 3 lysine 4 dimethylation, and histone 3 lysine 9 trimethylation in pertussis toxin (PTX)-induced thermal hyperalgesic rat spinal cords.
Male Wistar rats implanted with an intrathecal catheter received a single intrathecal PTX (1 μg in 5 μl saline) injection. Four days later, they were randomly assigned to receive either a single injection of saline, or ultra-low-dose naloxone (15 ng in 5 μl saline), followed by morphine (10 μg in 5 μl saline) injection 30 minutes later.
The results showed that PTX injection induced thermal hyperalgesia and significant increase of global histone methylation in the spinal cords. Intrathecal morphine alone did not affect the thermal hyperalgesia and global histone methylation. In contrast, intrathecal administration of ultra-low-dose naloxone plus morphine significantly attenuated the PTX-induced thermal hyperalgesia and down-regulated the global histone methylation.
The results suggest that ultra-low-dose naloxone might be clinical valuable for neuropathic pain management via regulating global histone modification.
Ultra-low dose naloxone restores the antinociceptive effect of morphine in pertussis toxin-treated rats by reversing the coupling of μ-opioid receptors from Gs-protein to coupling to Gi-protein
2009, Neuroscience
Pertussis toxin (PTX) treatment results in ADP-ribosylation of Gi-protein and thus in disruption of μ-opioid receptor signal transduction and loss of the antinociceptive effect of morphine. We have previously demonstrated that pretreatment with ultra-low dose naloxone preserves the antinociceptive effect of morphine in PTX-treated rats. The present study further examined the effect of ultra-low dose naloxone on μ-opioid receptor signaling in PTX-treated rats and the underlying mechanism. Male Wistar rats implanted with an intrathecal catheter received an intrathecal injection of saline or PTX (1 μg in 5 μl of saline), then, 4 days later, were pretreated by intrathecal injection with either saline or ultra-low dose naloxone (15 ng in 5 μl of saline), followed, 30 min later, by saline or morphine (10 μg in 5 μl of saline). Four days after PTX injection, thermal hyperalgesia was observed, together with increased coupling of excitatory Gs-protein to μ-opioid receptors in the spinal cord. Ultra-low dose naloxone pretreatment preserved the antinociceptive effect of morphine, and this effect was completely blocked by the μ-opioid receptor antagonist CTOP, but not by the κ-opioid receptor antagonist nor-BNI or the δ-opioid receptor antagonist naltrindole. Moreover, a co-immunoprecipitation study showed that ultra-low dose naloxone restored μ-opioid receptor/Gi-protein coupling and inhibited the PTX-induced μ-opioid receptor/Gs-protein coupling. In addition to the anti-neuroinflammatory effect and glutamate transporter modulation previously observed in PTX-treated rats, the re-establishment of μ-opioid receptor Gi/Go-protein coupling is involved in the restoration of the antinociceptive effect of morphine by ultra-low dose naloxone pretreatment by normalizing the balance between the excitatory and inhibitory signaling pathways. These results show that ultra-low dose naloxone preserves the antinociceptive effect of morphine, suppresses spinal neuroinflammation, and reduces PTX-elevated excitatory Gs-coupled opioid receptors in PTX-treated rats. We suggest that ultra-low dose naloxone might be clinically valuable in pain management.
Ultra-low dose naloxone restores the antinociceptive effect of morphine in pertussis toxin-treated rats and prevents glutamate transporter downregulation by suppressing the p38 mitogen-activated protein kinase signaling pathway
2009, Neuroscience
We previously demonstrated that ultra-low dose naloxone restores the antinociceptive effect of morphine in rats with pertussis toxin (PTX)–induced thermal hyperalgesia by reversing the downregulation of glutamate transporter (GT) expression and suppressing spinal neuroinflammation. In the present study, we examined the underlying mechanisms of this anti-inflammatory effect in PTX-treated rats, particularly on the expression of GTs. Male Wistar rats were implanted with an intrathecal catheter and, in some cases, with a microdialysis probe. All rats were injected intrathecally with saline (5 μl) or PTX (1 μg), then, 4 days later, were randomly assigned to receive a single injection of saline, ultra-low dose naloxone (15 ng), or the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (5 μg), followed by morphine injection (10 μg) 30 min later. Our results showed that PTX injection induced activation of microglia and a significant increase in P-p38 MAPK expression in the spinal cord. Ultra-low dose naloxone plus morphine significantly inhibited the effect of PTX on P-p38 MAPK expression in the spinal cord, while the p38 MAPK inhibitor SB203580 attenuated the PTX-induced mechanical allodynia, thermal hyperalgesia, increase in spinal cerebrospinal fluid excitatory amino acids, and downregulation of GTs. These results show that the restoration of the antinociceptive effect of morphine and GT expression in PTX-treated rats by ultra-low dose naloxone involves suppression of the p38 MAPK signal transduction cascade.
The analgesic efficacy of fentanyl: Relationship to tolerance and μ-opioid receptor regulation
2008, Pharmacology Biochemistry and Behavior
This study determined if fentanyl analgesic efficacy predicts the magnitude of tolerance and μ-opioid receptor regulation. To estimate efficacy, mice were injected i.p. with saline or clocinnamox (CCAM), an irreversible μ-opioid receptor antagonist, (0.32–25.6 mg/kg) and 24 h later fentanyl cumulative dose–response studies were conducted. CCAM dose dependently shifted the fentanyl dose–response function to the right. The apparent efficacy (τ) of fentanyl, based on the operational model of agonism, was estimated as 58, indicating that fentanyl is a high analgesic efficacy agonist. Next, mice were infused with fentanyl (1, 2 or 4 mg/kg/day) for 7 days. Controls were implanted with placebo pellets. At the end of 7 days, morphine cumulative dose–response studies or μ-opioid receptor saturation binding studies were conducted. Fentanyl infusions dose dependently decreased morphine potency with the highest fentanyl dose reducing morphine potency by ≈ 6 fold. Chronic infusion with fentanyl (4 mg/kg/day) significantly reduced μ-opioid receptor density by 28% without altering affinity, whereas lower infusion doses had no effect. Taken together, the present results strengthen the proposal that opioid analgesic efficacy predicts μ-opioid receptor regulation and the magnitude of tolerance.
Amitriptyline pretreatment preserves the antinociceptive effect of morphine in pertussis toxin-treated rats by lowering CSF excitatory amino acid concentrations and reversing the downregulation of glutamate transporters
2008, Brain Research
Citation Excerpt :
Intrathecal (i.t.) administration of pertussis toxin (PTX) caused hyperalgesia and allodynia that appears similar to the symptoms reported by patients suffering from neuropathic pain (McCormack et al., 1998). Activation of PTX-sensitive G proteins represents an essential step in the transduction mechanism underlying central antinociception (Galeotti et al., 1996) and PTX can be used as a probe to help uncover the cellular mechanisms of opioid actions (Shah et al., 1994). Following a further characterization of the PTX model, Womer et al. (1997) concluded that the i.t. PTX injection-induced persistent thermal hyperalgesia and allodynia are similar to other neuropathic pain models involving nerve ligation or section (Bennett and Xie, 1988; Kim and Chung, 1992; Wiesenfeld-Hallin, 1984), and they suggested that PTX-induced hyperalgesia and allodynia are not caused by a peripheral mechanism, but via a direct central mechanism (McCormack et al., 1998; Womer et al., 1997).
This study was designed to investigate the effect of acute intrathecal (i.t.) injection of amitriptyline (AMI) on the antinociceptive effect of morphine in rats treated with pertussis toxin (PTX). Male Wistar rats were implanted with an i.t. catheter for drug injection and some were implanted with an additional microdialysis probe used for CSF dialysate collection and measurement of excitatory amino acids (EAAs). The expression of glutamate transporters (GTs) in the spinal cord dorsal horn was also measured. A tail-flick test was performed and CSF dialysate was collected as the baseline-B value (day 0) before PTX (1 μg, i.t.) injection and at 4 days after PTX injection, but before drug challenge as the baseline-P value (day 4), and at 30, 60, 90, and 120 min after drug challenge on day 4. The baseline-P tail-flick latencies were significantly lower than the baseline-B values. In PTX-treated rats (day 4), morphine (10 μg, i.t.) did not produce an antinociceptive effect, but this was retained by acute AMI (15 μg, i.t.) pretreatment 30 min before morphine injection. In addition, concentrations of glutamate and aspartate were higher in baseline-P dialysates than in baseline-B dialysates, and the expression of the GTs (GLT-1, GLAST, and EAAC1) was downregulated by PTX treatment. Acute injection of PTX-treated rats with either AMI (15 μg, i.t.) or morphine (10 μg, i.t.) alone had no significant effect on CSF EAA concentrations and GT expression. In contrast, AMI (15 μg, i.t.) pretreatment followed 30 min later by morphine (10 μg, i.t.) injection inhibited the increase in EAA concentrations and reversed the downregulation of all three GTs. Our results show that AMI preserves the antinociceptive effect of morphine in PTX-treated rats. The mechanisms involve suppression of the increase in EAA concentrations in spinal CSF dialysates and reversion of GT expression in PTX-treated rats.

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Brief communicationSpinal and supraspinal effects of pertussis toxin on opioid analgesia

Abstract

Biochem. Biophys. Res. Commun.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Life Sci.

Eur. J. Pharmacol.

J. Biol. Chem.

Life Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Brief communication
Spinal and supraspinal effects of pertussis toxin on opioid analgesia