Resting and Evoked Spinal Substance P Release during Chronic Intrathecal Morphine Infusion: Parallels with Tolerance and Dependence

Gu, Guibao; Kondo, Isamu; Hua, Xiao‐Ying; Yaksh, Tony L.

doi:10.1124/jpet.105.087718

Cited by 38 publications

(45 citation statements)

References 43 publications

(64 reference statements)

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“…Because our anatomic observations (above) indicate that DRG neurons and their central terminals were unaffected by lumbar intrathecal Derm-sap and the behavioral data show decreased morphine antinociception in Derm-sap-treated rats, we interpret the present results as calling into question the hypothesis that morphine acts by inhibiting primary afferent terminals (Aimone and Yaksh, 1989;Ueda et al, 1995;Kondo et al, 2005). One difference between the present study and experiments that showed morphine inhibition of evoked spinal glutamate (Ibuki et al, 2003) and substance P release (Gu et al, 2005) is the use of high-intensity stimuli in the release experiments that would be expected to activate A␦ primary afferents. Also, the release experiments did not identify the cellular source of the glutamate and substance P. Further doubt about the importance of -opiate effects on primary afferent terminals comes from the observations that (1) internalization of MOR into dorsal horn neurons in response to -opiate agonists or Derm-sap (500 ng; n ϭ 6) in Sprague Dawley male rats.…”

Section: Discussioncontrasting

confidence: 54%

Spinal μ-Opioid Receptor-Expressing Dorsal Horn Neurons: Role in Nociception and Morphine Antinociception

Kline¹,

Wiley²

2008

J. Neurosci.

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The role of spinal cord -opioid receptor (MOR)-expressing dorsal horn neurons in nociception and morphine analgesia is incompletely understood. Using intrathecal dermorphin-saporin (Derm-sap) to selectively destroy MOR-expressing dorsal horn neurons, we sought to determine the role of these neurons in (1) normal baseline reflex nocifensive responses to noxious thermal stimulation (hotplate, tail flick) and to persistent noxious chemical stimulation (formalin) and (2) the antinociceptive activity of intrathecal and systemic morphine in the same tests. Lumbar intrathecal Derm-sap (500 ng) produced (1) partial loss of lamina II MOR-expressing dorsal horn neurons, (2) no effect on MOR-expressing dorsal root ganglion neurons, and (3) no change in baseline tail-flick and hotplate reflex nocifensive responses. Derm-sap treatment attenuated the antinociceptive action of both intrathecal and systemic morphine on hotplate responses. Derm-sap treatment had two effects in the formalin test: (1) increased baseline nocifensive responding and (2) reduced antinociceptive action of systemic morphine. We conclude that MOR-expressing dorsal horn neurons (1) are not essential for determining nocifensive reflex responsiveness to noxious thermal stimuli, (2) are necessary for full antinociceptive action of morphine (intrathecal or systemic) in these tests, and (3) play a significant role in the endogenous modulation of reflex nocifensive responses to persistent pain in the formalin test. Thus, one would predict that altering the activity of MOR-expressing dorsal horn neurons would be antinociceptive and of interest in the search for new approaches to management of chronic pain.

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Section: Discussioncontrasting

confidence: 54%

Spinal μ-Opioid Receptor-Expressing Dorsal Horn Neurons: Role in Nociception and Morphine Antinociception

Kline¹,

Wiley²

2008

J. Neurosci.

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“…As already discussed, enhanced nociception underlies both OIH and tolerance to some extent. Previous reports indicated that the levels of expression and release of these peptides are enhanced with chronic morphine administration, and that this enhanced expression and release of nociceptive peptides supports tolerance and OIH [16,25,37]. Another report provided data demonstrating that the spinal blockade of substance P and CGRP antagonists significantly reduced naloxone induced withdrawal symptoms in morphine dependent rats [44].…”

Section: Discussionmentioning

confidence: 81%

The β2 adrenergic receptor regulates morphine tolerance and physical dependence

Liang

Shi

et al. 2007

Behavioural Brain Research

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Adaptations to the chronic administration of opioids reduce the utility of these drugs in treating pain and support addiction. Recent genetics-based approaches have implicated the β2 adrenergic receptor (β2-AR) in controlling some of these responses. We do not know, however, whether this receptor can modulate tolerance, dependence or changes in gene expression caused by chronic opioid administration. For our studies we used C57BL/6 mice and β2-AR knockout mice in the FVB background. Morphine dose response relationships were established both prior to and after chronic morphine treatment. In some cases, the selective β2-AR antagonist butoxamine was administered along with or after morphine. Physical dependence was assessed using naloxone-precipitated withdrawal. The expression of calcitonin gene related peptide (CGRP) and substance P (SP) were measured in spinal cord and dorsal root ganglion (DRG) tissues using both real-time PCR and enzyme-linked immunoassay (ELISA). Both the co-administration of butoxamine with morphine and the administration of butoxamine after chronic morphine reversed morphine tolerance. Morphine failed to cause tolerance in β2-AR knockout mice. Physical dependence was reduced under the same circumstances. The chronic administration of butoxamine with morphine reduced or eliminated the normally observed up-regulation of CGRP and SP in spinal cord and DRG tissues. Our results suggest that the β2-AR modulates both opioid tolerance and physical dependence. Activation of β2-ARs appears to be required for some of the key neurochemical changes which characterize chronic opioid administration. Therefore β2-AR antagonists show some promise as agents to enhance chronic opioid analgesic therapy.

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“…In the current study and that by Afrah et al (2001), spinal NMDA was applied to anesthetized rats, which resulted in a lack of NMDA-induced SP release and NK1r internalization. Although plausible, it is unlikely that the anesthetic was directly responsible for the differences in NK1r internalization, because i) the same anesthetic protocol did not prevent release from peripheral noxious stimuli, such as paw compression or intraplantar formalin (Honore et al, 1999;Trafton et al, 2001;Gu et al, 2005;Kondo et al, 2005); and ii) in the present study, intrathecal morphine did reduce the formalin-induced NK1r internalization, whereas, intrathecal capsaicin evoked NK1r internalization, indicating that presynaptic modulation of SP release has not been abolished by the anesthetic. Thus, NMDAinduced NK1r internalization demonstrated by Liu et al (1997) could be due to a secondary effect of NMDA-induced hyperexcitability at spinal and super-spinal levels in awake rats.…”

mentioning

confidence: 54%

Spinal N-methyl-d-aspartate receptors and nociception-evoked release of primary afferent substance P

Nazarian

Gracias

et al. 2008

Neuroscience

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Dorsal horn NMDA receptors contribute significantly to spinal nociceptive processing through an effect postsynaptic to non-primary glutamatergic axons, and perhaps presynaptic to the primary afferent terminals. The present study sought to examine the regulatory effects of NMDA receptors on primary afferent release of SP, as measured by neurokinin 1 receptor (NK1r) internalization in the spinal dorsal horn of rats. The effects of intrathecal NMDA alone or in combination with D-serine (a glycine site agonist) was initially examined on basal levels of NK1r internalization. NMDA alone or when co-administered with D-serine failed to induce NK1r internalization, whereas activation of spinal TRPV1 receptors by capsaicin resulted in a notable NK1r internalization. To determine whether NMDA receptor activation could potentiate NK1r internalization or pain behavior induced by a peripheral noxious stimulus, intrathecal NMDA was given prior to an intraplantar injection of formalin. NMDA did not alter the formalin-induced NK1r internalization nor did it enhance the formalin paw flinching behavior. To further characterize the effects of presynaptic NMDA receptors, the NMDA antagonists AP-5 and MK-801 were intrathecally administered to assess their regulatory effects on formalin-induced NK1r internalization and pain behavior. AP-5 had no effect on formalininduced NK1r internalization, whereas MK-801 produced only a modest reduction. Both antagonists, however, reduced the formalin paw flinching behavior. In subsequent in vitro experiments, perfusion of NMDA in spinal cord slice preparations did not evoke basal release of SP or calcitonin generelated peptide (CGRP). Likewise, perfusion of NMDA did not enhance capsaicin-evoked release of the two peptides. These results suggest that presynaptic NMDA receptors in the spinal cord play little if any role on the primary afferent release of SP. KeywordsNeurokinin 1 receptor; internalization; dorsal horn; glutamate; C-fiber *Correspondence should be addressed to: Dr. Arbi Nazarian, Department of Pharmaceutical Sciences, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766-1854, Tel: (909) Fax: (909) 469-5600, Email: anazarian@westernu.edu. a These authors have contributed equally to this manuscript. Section Editor: Dr. Richard J. Weinberg, Department of Cell and Developmental Biology, CB7090, University of North Carolina, Chapel Hill, NC, 27599 USA Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Small diameter primary afferents terminate superficially in lamina I and II and exert frequencydependent depolarizin...

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Resting and Evoked Spinal Substance P Release during Chronic Intrathecal Morphine Infusion: Parallels with Tolerance and Dependence

Cited by 38 publications

References 43 publications

Spinal μ-Opioid Receptor-Expressing Dorsal Horn Neurons: Role in Nociception and Morphine Antinociception

Spinal μ-Opioid Receptor-Expressing Dorsal Horn Neurons: Role in Nociception and Morphine Antinociception

The β2 adrenergic receptor regulates morphine tolerance and physical dependence

Spinal N-methyl-d-aspartate receptors and nociception-evoked release of primary afferent substance P

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