A novel interaction between dynorphin(1–13) and an N-methyl-d-aspartate site

doi:10.1016/0006-8993(88)91628-9

Brain Research

Volume 443, Issues 1–2, 8 March 1988, Pages 329-332

https://doi.org/10.1016/0006-8993(88)91628-9 Get rights and content

Abstract

Dynorphin injected intrathecally in the rat results in a neurotoxicity behaviorally expressed as an irreversible loss of the thermally evoked tail-flick. The excitatory amino acid antagonists dl-2-amino-5-phosphonovalerate (APV) and γ-d-glutamylglycine (DGG) blocked the loss of the tail-flick reflex. The order of potency (APV > DGG) suggests that the $N- methyl- d -aspartate$ (NMDA) subclass of excitatory amino acid receptors participate in the neurotoxicity. Additionally, intrathecal injection of APV results in a reversible loss of the tail-flick reflex, whereas with DGG doses which block the tail-flick reflex also result in hindlimb paralysis. These data suggest that neurotransmission in the tail-flick reflex pathway is, in part, mediated by NMDA receptors. From these and previous findings it was concluded that dynorphin neurotoxicity resuls from enhanced, excitotoxic, transmission across these synapses utilizing NMDA receptors.

References (25)

J.A. Bell et al.
The effect of the narcotic antagonists natrexone and nalorphine on spinal cord C-fiber reflexes evoked by electrical stimulation or radiant heat
Eur. J. Pharmacol.
(1977)
J. Davies
Effects of morphine and naloxone on Renshaw cells and interneurones in morphine dependent and non-dependent rats
Brain Research
(1976)
A.I. Faden et al.
Motor spinal cord injury is mediated by opiate receptors
Peptides
(1985)
H.C. Moises et al.
Electrophysiological effects of dynorphin peptides on hippocampal pyramidal cells in rat
Eur. J. Pharmacol.
(1985)
R. Przewlocki et al.
Characterization and localization of immunoreactive dynorphin, α-neo-endophin, Met-enkephalin, and substance P in human spinal cord
Brain Research
(1983)
S. Spampinato et al.
Characterization of dynorphin A-induced antinociception at spinal levels
Eur. J. Pharmacol.
(1985)
N. Zamir et al.
Distribution of immunoreactive dynorphin B in discrete areas of the brain and spinal cord
Brain Research
(1984)
J.L. Barker et al.
Opiate modulation of amino acid responses suggests novel form of neuronal communication
Science
(1978)
A.I. Basbaum et al.
Immunoreactive dynorphin B sacral primary afferent fibers of the cat
J. Neurosci.
(1986)
Caudle, R.M. and Isaac, L., Intrathecal dynorphin(1–13) results in an irreversible loss of the tail-flick reflex in the...

Caudle, R.M. and Isaac, L., The mechanism of dynorphin(1–13) induced neurotoxicity in the spinal cord of the rat,...

C. Chavkin et al.

Dynorphin is an endogenous ligand of the κ opioid receptor

Science

(1982)

Cited by (85)

Dynorphin and Enkephalin Opioid Peptides and Transcripts in Spinal Cord and Dorsal Root Ganglion During Peripheral Inflammatory Hyperalgesia and Allodynia
2020, Journal of Pain
Understanding molecular alterations associated with peripheral inflammation is a critical factor in selectively controlling acute and persistent pain. The present report employs in situ hybridization of the 2 opioid precursor mRNAs coupled with quantitative measurements of 2 peptides derived from the prodynorphin and proenkephalin precursor proteins: dynorphin A 1-8 and [Met⁵]-enkephalin-Arg⁶-Gly⁷-Leu⁸. In dorsal spinal cord ipsilateral to the inflammation, dynorphin A 1-8 was elevated after inflammation, and persisted as long as the inflammation was sustained. Qualitative identification by high performance liquid chromatography and gel permeation chromatography revealed the major immunoreactive species in control and inflamed extracts to be dynorphin A 1-8. In situ hybridization in spinal cord after administration of the inflammatory agent, carrageenan, showed increased expression of prodynorphin (Pdyn) mRNA somatotopically in medial superficial dorsal horn neurons. The fold increase in preproenkephalin mRNA (Penk) was comparatively lower, although the basal expression is substantially higher than Pdyn. While Pdyn is not expressed in the dorsal root ganglion (DRG) in basal conditions, it can be induced by nerve injury, but not by inflammation alone. A bioinformatic meta-analysis of multiple nerve injury datasets confirmed Pdyn upregulation in DRG across different nerve injury models. These data support the idea that activation of endogenous opioids, notably dynorphin, is a dynamic indicator of persistent pain states in spinal cord and of nerve injury in DRG.
This is a systematic, quantitative assessment of dynorphin and enkephalin peptides and mRNA in dorsal spinal cord and DRG neurons in response to peripheral inflammation and axotomy. These studies form the foundational framework for understanding how endogenous spinal opioid peptides are involved in nociceptive circuit modulation.
Opioid administration following spinal cord injury: Implications for pain and locomotor recovery
2013, Experimental Neurology
Citation Excerpt :
Sustained opioid administration results in increased spinal levels of dynorphin (see Vanderah et al., 2001). Dynorphin is often pronociceptive (Caudle and Isaac, 1988; Cho and Basbaum, 1989; Dubner and Ruda, 1992; Kajander et al., 1990; Wang et al., 2001), and, via a non-opioid mechanism, results in the release of excitatory amino acids (Faden, 1992). Faden (1992) demonstrated that administration of both the opioid-active dynorphin 1–17 and the opioid inactive dynorphin 2–17 results in similar levels of glutamate and aspartate release in intact rats, which are not blocked by opioid receptor antagonists.
Approximately one-third of people with a spinal cord injury (SCI) will experience persistent neuropathic pain following injury. This pain negatively affects quality of life and is difficult to treat. Opioids are among the most effective drug treatments, and are commonly prescribed, but experimental evidence suggests that opioid treatment in the acute phase of injury can attenuate recovery of locomotor function. In fact, spinal cord injury and opioid administration share several common features (e.g. central sensitization, excitotoxicity, aberrant glial activation) that have been linked to impaired recovery of function, as well as the development of pain. Despite these effects, the interactions between opioid use and spinal cord injury have not been fully explored. A review of the literature, described here, suggests that caution is warranted when administering opioids after SCI. Opioid administration may synergistically contribute to the pathology of SCI to increase the development of pain, decrease locomotor recovery, and leave individuals at risk for infection. Considering these negative implications, it is important that guidelines are established for the use of opioids following spinal cord and other central nervous system injuries.
Endogenous dynorphins, glutamate and N-methyl-d-aspartate (NMDA) receptors may participate in a stress-mediated Type-I auditory neural exacerbation of tinnitus
2013, Brain Research
Citation Excerpt :
In addition to this, dynorphins are often involved in an excitotoxic/neurotoxic activation at NMDA receptors (Skilling et al., 1992), producing a long-lasting sensitivity to completely innocuous stimuli in the presence of dynorphins, a sensitivity that is mediated through NMDA receptors (Laughlin et al., 1997; Vanderah et al., 1996). In short, an observed neural hypersensitivity and hyperactivation arises through a κ-opioid receptor-mediated facilitation of NMDA receptor sensitivity to glutamate (Caudle and Isaac, 1988; Dubner, 1992; Dubner and Ruda, 1992; Shukla and Lemaire, 1994). Hence, under pathological conditions, a stress-induced hypersensitivity to innocuous stimuli, activated by dynorphins at glutamate-sensitive NMDA receptors (Laughlin et al., 1997; Tan-No et al., 2002), appears comparable to the reported augmentation in auditory neural sensitivity to synchronous, low amplitude (innocuous) stimuli that is often associated with tinnitus, and this heightened sensitivity is commonly referred to as “hyperacusis”.
Tinnitus is the phantom perception of sounds occurring in the absence of an external auditory stimulus. Tinnitus: [1] effects 50 million individuals, [2] often results from acoustic trauma and, [3] is very often exacerbated under stressful conditions. Tinnitus may result from lesions occurring at any location in the auditory system, but its mechanisms are poorly understood. Evidence is provided supporting an endogenous dynorphin-mediated potentiation of glutamate excitotoxicity at cochlear Type-I auditory dendrites that may well exacerbate chronic subjective neural-generated tinnitus during periods of heightened stress. The proposed mechanism is based on the following: [1] lateral efferent olivocochlear (LEOC) axon terminals contain endogenous dynorphin neuromodulators and are presynaptic to cochlear Type-I auditory dendrites that bear both κ-opioid and N-methyl-d-aspartate (NMDA) receptors/binding sites; [2] the release of presynaptic LEOC dynorphins is likely to be triggered by sympathetic stress via the locus coeruleus; [3] sodium salicylate induces an acute excitotoxicity by potentiating glutamate neurotransmitter effects at cochlear NMDA receptors, resulting in a Type-I auditory neural-generated tinnitus; [4] dynorphins participate in central NMDA-receptor-mediated excitotoxic inflammation; and [5] κ-opioid receptor ligands also modulate Type-I auditory neural activity by potentiating glutamate at cochlear NMDA receptors. A stress-activated release of dynorphins into the cochlea could potentiate the already excitotoxic effects of glutamate, producing: [1] hyperacusis, together with an acute exacerbation of [2] chronic aberrant Type-I neural activity and [3] a worsening of the activity-dependent central auditory neural plasticity changes that must certainly generate the perception of tinnitus. Treatment options are discussed.
The role of nociceptin and dynorphin in chronic pain: Implications of neuro-glial interaction
2011, Neuropeptides
Citation Excerpt :
Moreover, DYN plays an essential role in the sensitisation of nociceptive neurons at the spinal level, which is also similar to the role of NOC. Indeed, intrathecal administration of DYN has been demonstrated to alter C-fiber reflexes and increase the receptive field size of dorsal horn neurons during hindpaw mechanical stimulation (Caudle and Isaac, 1988). However, it is interesting that whereas both NOC and DYN display inhibitory and excitatory actions at the spinal level, the dose range leading to these effects is contradictory.
Nociceptin-opioid peptide (NOP) receptor, also known as opioid receptor like-1 (ORL1), was identified following the cloning of the kappa-opioid peptide (KOP) receptor, and the characterization of these receptors revealed high homology. The endogenous ligand of NOP, nociceptin (NOC), which shares high homology to dynorphin (DYN), was discovered shortly thereafter, and since then, it has been the subject of several investigations. Despite the many advances in our understanding of the involvement of NOC and DYN systems in pain, tolerance and withdrawal, the precise function of these systems has not been fully characterized. Here, we review the recent literature concerning the distribution of the NOC and DYN systems in the central nervous system and the involvement of these systems in nociceptive transmission, especially under chronic pain conditions. We discuss the use of endogenous and exogenous ligands of NOP and KOP receptors in pain perception, as well as the potential utility of NOP ligands in clinical practice for pain management. We also discuss the modulation of opioid effects by NOC and DYN. We emphasize the important role of neuro–glial interactions in the effects of NOC and DYN, focusing on their presence in neuronal and non-neuronal cells and the changes associated with chronic pain conditions. We also present the dynamics of immune and glial regulation of neuronal functions and the importance of this regulation in the roles of NOC and DYN under conditions of neuropathic pain and in the use of drugs that alter these systems for better control of neuropathic pain.
30 years of dynorphins - New insights on their functions in neuropsychiatric diseases
2009, Pharmacology and Therapeutics
Since the first description of their opioid properties three decades ago, dynorphins have increasingly been thought to play a regulatory role in numerous functional pathways of the brain. Dynorphins are members of the opioid peptide family and preferentially bind to kappa opioid receptors. In line with their localization in the hippocampus, amygdala, hypothalamus, striatum and spinal cord, their functions are related to learning and memory, emotional control, stress response and pain. Pathophysiological mechanisms that may involve dynorphins/kappa opioid receptors include epilepsy, addiction, depression and schizophrenia. Most of these functions were proposed in the 1980s and 1990s following histochemical, pharmacological and electrophysiological experiments using kappa receptor-specific or general opioid receptor agonists and antagonists in animal models. However, at that time, we had little information on the functional relevance of endogenous dynorphins. This was mainly due to the complexity of the opioid system. Besides actions of peptides from all three classical opioid precursors (proenkephalin, prodynorphin, proopiomelanocortin) on the three classical opioid receptors (delta, mu and kappa), dynorphins were also shown to exert non-opioid effects mainly through direct effects on NMDA receptors. Moreover, discrepancies between the distribution of opioid receptor binding sites and dynorphin immunoreactivity contributed to the difficulties in interpretation. In recent years, the generation of prodynorphin- and opioid receptor-deficient mice has provided the tools to investigate open questions on network effects of endogenous dynorphins.
This article examines the physiological, pathophysiological and pharmacological implications of dynorphins in the light of new insights in part obtained from genetically modified animals.
Inhibition of glutamate carboxypeptidase II (NAALADase) protects against dynorphin A-induced ischemic spinal cord injury in rats
2005, European Journal of Pharmacology
Glutamate carboxypeptidase (GCP) II (EC 3.4.17.21), which is also known as N-acetylated-α-linked acidic dipeptidase (NAALADase), hydrolyses the endogenous acidic dipeptide N-acetylaspartylglutamate (NAAG), yielding N-acetyl-aspartate and glutamate. Inhibition of this enzyme by 2-(phosphonomethyl) pentanedioic acid (2-PMPA) has been shown to protect against ischemic injury to the brain and hypoxic and metabolic injury to neuronal cells in culture, presumably by increasing and decreasing the extracellular concentrations of NAAG and glutamate, respectively. Since both NAAG and GCP II are found in especially high concentrations in the spinal cord, injuries to the spinal cord involving pathophysiological elevations in extracellular glutamate might be particularly responsive to GCP II inhibition. Lumbar subarachnoid injections of dynorphin A in rats cause ischemic spinal cord injury, elevated extracellular glutamate and a persistent hindlimb paralysis that is mediated through excitatory amino acid receptors. We therefore used this injury model to evaluate the protective effects of 2-PMPA. When coadministered with dynorphin A, 2-PMPA significantly attenuated the dynorphin A-induced elevations in cerebrospinal fluid glutamate levels and by 24 h postinjection caused significant dose-dependent improvements in motor scores that were associated with marked histopathological improvements. These results indicate that 2-PMPA provides effective protection against excitotoxic spinal cord injury.

View all citing articles on Scopus

View full text

Short communicationA novel interaction between dynorphin(1–13) and an N-methyl-d-aspartate site

Abstract

Eur. J. Pharmacol.

Brain Research

Peptides

Eur. J. Pharmacol.

Brain Research

Eur. J. Pharmacol.

Brain Research

Opiate modulation of amino acid responses suggests novel form of neuronal communication

Science

Immunoreactive dynorphin B sacral primary afferent fibers of the cat

J. Neurosci.

Dynorphin is an endogenous ligand of the κ opioid receptor

Science

Short communication
A novel interaction between dynorphin(1–13) and an $N- methyl- d -aspartate$ site