Bovine adrenal medulla 22 reverses antinociceptive morphine tolerance in the rat

doi:10.1016/j.bbr.2005.11.002

Behavioural Brain Research

Volume 168, Issue 1, 15 March 2006, Pages 167-171

https://doi.org/10.1016/j.bbr.2005.11.002 Get rights and content

Abstract

Acute intrathecal (i.t.) bovine adrenal medulla 22 (BAM22, 10 nmol), an endogenous opioid peptide, induced equipotent thermal antinociception in naïve and morphine-tolerant rats while chronic BAM22 resulted in hyperalgesia and decrease in the effectiveness of antinociception. In rats made tolerant to morphine, prior administration of BAM22 (10 nmol, i.t.) significantly resumed antinociceptive response of morphine. The present study demonstrated that BAM22 was able to modulate maintenance of morphine tolerance.

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Acknowledgements

This study was supported by the National Nature Science Foundation of China (30470565) and Natural Science Foundation of Fujian Province of China (C0410007).

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Cited by (17)

Chronic activation of Mas-related gene receptors (Mrg) reduces the potency of morphine-induced analgesia via PKC pathway in naive rats
2019, Brain Research
Mas oncogene-related gene receptors (Mrg) are uniquely distributed in small and medium cells of trigeminal and dorsal root ganglia (DRG). The physiological and pharmacological properties of Mrg are unknown. We have shown that intermittent activation of MrgC prevents and reverses morphine tolerance. Now we observed that intrathecal (i.t.) administration of the MrgC agonist bovine adrenal medulla 8–22 (BAM8-22, 3 nmol) for 3 and 6 days reduced the potency of morphine analgesia by 1.5 and 3.5 folds, respectively. Daily administration of BAM8-22 for 6 days also significantly decreased the tail flick latency. The administration of another MrgC agonist (Tyr⁶)-γ2-MSH-6–12 (MSH, 3 nmol) reduced morphine potency and the reduction was abolished following the co-administration of the protein kinase C (PKC) inhibitor chelerythrine chloride (CLT, 3 nmol). The chronic treatment with BAM8-22 or MSH increased the expression of PKC-gamma (PKCγ) in the cell membrane of spinal dorsal horn neurons and PKC-epsilon (PKCε) in the cell membrane and cytosol of DRG neurons. Moreover, the BAM8-22 treatment induced an increase in the expression of calcitonin gene-related peptide (CGRP) and neuronal nitric oxide synthase (nNOS) in small and medium cells in DRG. All of these responses were not seen when BAM8-22 or MSH was co-administered with the PKC inhibitor CLT (3 nmol) or GF-109203X (10 nmol). The present study suggested that the chronic activation of MrgC upregulated expressions of pronociceptive mediators via PKC signaling pathway leading to the suppression of antinociceptive property of morphine. These effects are opposite to those occurred when MrgC is activated acutely or moderately.
Upregulation of pronociceptive mediators and downregulation of opioid peptide by adrenomedullin following chronic exposure to morphine in rats
2014, Neuroscience
Citation Excerpt :
The present study was designed to examine the hypothesis that the peptide AM is one of the upstreams in a cascade that occurs in chronic morphine. As the opioid peptide bovine adrenal medulla 22 (BAM22) is involved in the development of morphine tolerance (Jiang et al., 2006; Chen et al., 2008), effect of inhibition of AM receptor signaling on morphine-induced change of BAM22 was also determined. Adult male Sprague–Dawley rats (250–320 g; Animal Center of Fujian Medical University, Fuzhou, China) were housed individually at 22 °C with 50 % humidity under a 12-h light/dark cycle and were given free access to food and water.
Adrenomedullin (AM) belongs to a calcitonin gene-related peptide (CGRP) family and has been demonstrated to recruit CGRP following chronic use of morphine and neuronal nitric oxide synthase (nNOS) in inflammation. The present study investigated the possibility that AM initiates the changes of other molecules contributing to the development of morphine tolerance in its chronic use. Intrathecal (i.t.) co-administration of the AM receptor antagonist AM_22–52 (35.8 μg) inhibited tolerance to morphine-induced analgesia while a daily injection of the AM receptor agonist AM_1–50 (8 μg, i.t., bolus) for 9 days induced a decrease in the potency of morphine analgesia and thermal hyperalgesia. Persistent exposure of cultured dorsal root ganglion (DRG) explants to morphine (3.3 μM) for 4 days resulted in an increase in AM and CGRP mRNA levels. However, morphine failed to produce these effects in the presence of AM_22–52 (2 μM). The i.t. administration of morphine for 6 days increased the expression of nNOS in the spinal dorsal horn and DRG neurons but decreased expression of the endogenous opioid peptide bovine adrenal medulla 22 (BAM22) in small- and medium-sized neurons in DRG. Particularly, the co-administration of AM_22–52 (35.8 μg) inhibited the morphine-induced alterations in nNOS and BAM22. These results indicated that the increase in nNOS and CGRP expressions and the decrease in BAM22 were attributed to the increased AM receptor signaling induced by chronic morphine. The present study supports the hypothesis that the enhancement of AM bioactivity triggered upregulation of pronociceptive mediators and downregulation of pain-inhibiting molecule in a cascade contributing to the development of morphine tolerance.
Activation of Mas oncogene-related gene (Mrg) C receptors enhances morphine-induced analgesia through modulation of coupling of μ-opioid receptor to Gi-protein in rat spinal dorsal horn
2013, Neuroscience
Mas oncogene-related gene (Mrg) G protein-coupled receptors are exclusively expressed in small-sized neurons in trigeminal and dorsal root ganglia (DRG) in mammals. The present study investigated the effect of MrgC receptor activation on morphine analgesic potency and addressed its possible mechanisms. Intrathecal (i.t.) administration of the specific MrgC receptor agonist bovine adrenal medulla 8-22 (BAM8-22, 3 nmol) increased morphine-induced analgesia and shifted the morphine dose–response curve to the left in rats. Acute morphine (5 μg) reduced the coupling of μ-opioid receptors (MORs) to Gi-, but not Gs-, protein in the spinal dorsal horn. The i.t. BAM8-22 (3 nmol) prevented this change of G-protein repertoire while the inactive MrgC receptor agonist BAM8-18 (3 nmol, i.t.) failed to do so. A double labeling study showed the co-localization of MrgC and MORs in DRG neurons. The i.t. BAM8-22 also increased the coupling of MORs to Gi-protein and recruited Gi-protein from cytoplasm to the cell membrane in the spinal dorsal horn. Application of BAM8-22 (10 nM) in the cultured ganglion explants for 30 min increased Gi-protein mRNA, but not Gs-protein mRNA. The present study demonstrated that acute administration of morphine inhibited the repertoire of MOR/Gi-protein coupling in the spinal dorsal horn in vivo. The findings highlight a novel mechanism by which the activation of MrgC receptors can modulate the coupling of MORs with Gi-protein to enhance morphine-induced analgesia. Hence, adjunct treatment of MrgC agonist BAM8-22 may be of therapeutic value to relieve pain.
Role of bovine adrenal medulla 22 (BAM22) in the pathogenesis of neuropathic pain in rats with spinal nerve ligation
2012, European Journal of Pharmacology
Citation Excerpt :
In other words, our results suggest that the induction of neuropathic pain is partially attributed to the loss of protective effect of BAM22. This is similar to the contribution of BAM22 reduction to the development of morphine tolerance (Chen et al., 2008; Jiang et al., 2006). The present study supports the notion that a loss of antinociceptive activity reduces the counteraction against pronociceptive mediators, strengthening the severity of neuropathic pain.
The opioid peptide bovine adrenal medulla 22 (BAM22) is a cleavage product of proenkephalin and has been shown to be involved in inflammatory pain and morphine tolerance. This study was designed to investigate a role of BAM22 in neuropathic pain. L5 spinal nerve ligation (SNL) significantly reduced BAM22-immunoreactivity in small-sized neurons and depleted IB4 binding in injured L5 dorsal root ganglia (DRG) compared to sham rats. Double labeling study showed that the expression of BAM22-immunoreactivity was decreased mainly in IB4 neurons in the neighboring intact L4 and L6 DRGs following SNL. The nerve injury dramatically increased sensitivity of hindpaw to mechanical stimulation. Intrathecal (i.t.) administration of BAM22 on day 10 post-SNL attenuated mechanical allodynia in a dose-dependent manner (3–30 nmol) and the effect lasted for up to 90 min. Similar treatment with morphine at a dose of 30 nmol produced a mild and brief inhibition on pain hypersensitivity. Furthermore, i.t. administration of 30 nmol of BAM22 suppressed SNL-induced upregulation of interleukin-1β (IL-1β) in the spinal dorsal horn. The present study suggests that the reduction of BAM22 expression in small-sized neurons in both injured and the adjacent DRGs may contribute to pain hypersensitivity in peripheral nerve injury as a result of loss of inhibition of IL-1β upregulation in the spinal dorsal horn. Our results support the hypothesis that a reduction of antinociceptive activity loses the counteraction against activity of pronociceptive mediators, enhancing pain hypersensitivity following peripheral nerve injury.
Dual modulation effects of Mas-related gene (Mrg) receptors on pain sensitivity in rats
2012, Neuroscience Letters
Mas-related gene G protein-coupled (Mrg) receptors have been identified to be uniquely distributed in subpopulations of small-diameter neurons in dorsal root and trigeminal ganglia in rodents and humans. It has been demonstrated that the activation of MrgC receptors in rodents inhibits pathological pain but does not alter pain sensitivity under normal conditions. In vitro studies have suggested that the activation of MrgX1 or MrgD receptors is associated with dual G proteins. The current study was designed to determine whether rat MrgC receptors are coupled to Gi/o and Gq proteins and what pain behavior response activation of these proteins could mediate. Intrathecal (i.t.) administration of bovine adrenal medulla 8-22 (BAM8-22), a specific MrgC receptor agonist, dose-dependently decreased tail flick latency (TFL) in rats pretreated with pertussis toxin, but not with saline. On the other hand, i.t. injected BAM8-22 increased TFL in the presence of U73122 but produced no changes in TFL following pretreatment with saline. The results in the present study provide in vivo evidence that both Gi/o and Gq proteins are involved in MrgC receptor signaling.
Blockade of adrenomedullin receptors reverses morphine tolerance and its neurochemical mechanisms
2011, Behavioural Brain Research
Citation Excerpt :
Intracerebroventricular or i.t. administration of BAM22 inhibits urinary bladder reflex contractions [9], tail-flick reflex and formalin-induced nocifensive response [15] as well as spinal Fos expression [50] in a naloxone-reversed manner. We have observed that the insufficiency of this peptide contributes to the maintenance of morphine tolerance as exogenous administration of BAM22 resumes antinociceptive property of morphine [18]. This finding is in agreement with the study showing that the long-term exposure to morphine reduces the expression of BAM22 in superficial layers of the spinal cord [7].
Adrenomedullin (AM) has been demonstrated to be involved in the development of opioid tolerance. The present study further investigated the role of AM in the maintenance of morphine tolerance, morphine-associated hyperalgesia and its cellular mechanisms. Intrathecal (i.t.) injection of morphine for 6 days induced a decline of its analgesic effect and hyperalgesia. Acute administration of the AM receptor antagonist AM_22–52 resumed the potency of morphine in a dose-dependent manner (12, 35.8 and 71.5 μg, i.t.). The AM_22–52 treatment also suppressed morphine tolerance-associated hyperalgesia. Furthermore, i.t. administration of AM_22–52 at a dose of 35.8 μg reversed the morphine induced-enhancement of nNOS (neuronal nitric oxide synthase) and CGRP immunoreactivity in the spinal dorsal horn and/or dorsal root ganglia (DRG). Interestingly, chronic administration of morphine reduced the expression of the endogenous opioid peptide bovine adrenal medulla 22 (BAM22) in small- and medium-sized neurons in DRG and this reduction was partially reversed by the administration of AM_22–52 (35.8 μg). These results suggest that the activation of AM receptors was involved in the maintenance of morphine tolerance mediating by not only upregulation of the pronociceptive mediators, nNOS and CGRP but also the down-regulation of pain-inhibiting molecule BAM22. Our data support the hypothesis that the level of both pronociceptive mediators and endogenous pain-inhibiting molecules has an impact on the potency of morphine analgesia. Targeting AM receptors is a promising approach to maintain the potency of morphine analgesia during chronic use of this drug.

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Short communicationBovine adrenal medulla 22 reverses antinociceptive morphine tolerance in the rat

Abstract

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Acknowledgements

Life Sci

Peptides

Eur J Pharmacol

Neurosci Lett

Brain Res

Physiol Behav

Eur J Pharmacol

Eur J Pharmacol

Neuron

Life Sci

The molecular evolution of neuropeptides: prospects for the 90s

Brain Behav Evol

Short communication
Bovine adrenal medulla 22 reverses antinociceptive morphine tolerance in the rat