Induction of Synaptic Long-Term Potentiation After Opioid Withdrawal

Drdla, Ruth; Gassner, Matthias; Gingl, Ewald; Sandkühler, Jürgen

doi:10.1126/science.1171759

Cited by 184 publications

(200 citation statements)

References 27 publications

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“…LTP at glutamatergic C-fiber synapses onto lamina I projection neurons has been extensively studied as a cellular mechanism accompanying hyperalgesia (18,(46)(47)(48), but relatively little is known about plasticity at dorsal horn inhibitory synapses (49). To our knowledge, the LTP we describe here is the first example of LTP at glycinergic synapses in the mammalian CNS.…”

Section: Discussionmentioning

confidence: 81%

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Chirila

Brown

Bishop

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Long-term potentiation (LTP) is a persistent increase in synaptic strength required for many behavioral adaptations, including learning and memory, visual and somatosensory system functional development, and drug addiction. Recent work has suggested a role for LTP-like phenomena in the processing of nociceptive information in the dorsal horn and in the generation of central sensitization during chronic pain states. Whereas LTP of glutamatergic and GABAergic synapses has been characterized throughout the central nervous system, to our knowledge there have been no reports of LTP at mammalian glycinergic synapses. Glycine receptors (GlyRs) are structurally related to GABA A receptors and have a similar inhibitory role. Here we report that in the superficial dorsal horn of the spinal cord, glycinergic synapses on inhibitory GABAergic neurons exhibit LTP, occurring rapidly after exposure to the inflammatory cytokine interleukin-1 beta. This form of LTP (GlyR LTP) results from an increase in the number and/or change in biophysical properties of postsynaptic glycine receptors. Notably, formalin-induced peripheral inflammation in vivo potentiates glycinergic synapses on dorsal horn neurons, suggesting that GlyR LTP is triggered during inflammatory peripheral injury. Our results define a previously unidentified mechanism that could disinhibit neurons transmitting nociceptive information and may represent a useful therapeutic target for the treatment of pain.G lycine mediates fast synaptic inhibition throughout the spinal cord, brainstem, and midbrain, controlling normal motor behavior and rhythm generation, somatosensory processing, auditory and retinal signaling, and coordination of reflex responses (1). Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels of the Cys-loop receptor family that together with GABA A receptors (GABA A Rs) dynamically interact with the synaptic scaffold protein gephyrin to form inhibitory synapses (1, 2). In the dorsal horn of the spinal cord, glycinergic synapses are essential for nociceptive and tactile sensory processing both during adaptive and pathological pain states (3-7). However, compared with glutamatergic and GABAergic synapses, little is known about the regulation of their synaptic strength. Several studies have examined glycine receptor trafficking in cultured neurons and in heterologous expression systems (8, 9). Intracellular Ca 2+ appears important in the stabilization of GlyRs at synapses in culture (10), and elevation of intracellular Ca 2+ can also potently increase glycine receptor single channel openings in cultured cells and in heterologous systems (11). However, the modulation of glycinergic synaptic strength in native tissue remains relatively unexplored.Following peripheral injury or inflammation, changes in tactile perception develop, including hyperalgesia (exaggerated pain upon noxious stimulation), allodynia (pain in response to innocuous stimuli), and secondary hyperalgesia (pain spreading beyond the confines of the injure...

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Section: Discussionmentioning

confidence: 81%

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Chirila

Brown

Bishop

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…It is intriguing to note that these adaptations are only observed after intermittent morphine exposure, and not following continuous exposure (Fitzgerald et al, 1996). The offset of opiate action has recently been shown to be a potent stimulus for synaptic plasticity in the spinal cord (Drdla et al, 2009). The development of psychomotor sensitization is associated with multiple forms of synaptic plasticity in the mesolimbic dopamine system (Kauer and Malenka, 2007), raising the possibility that the offset of drug action drives some of these forms of plasticity.…”

Section: Discussionmentioning

confidence: 99%

Episodic Withdrawal Promotes Psychomotor Sensitization to Morphine

Rothwell

Gewirtz

Thomas

2010

Neuropsychopharmacol

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The relative intermittency or continuity of drug delivery is a major determinant of addictive liability, and also influences the impact of drug exposure on brain function and behavior. Events that occur during the offset of drug action (ie, acute withdrawal) may have an important role in the consequences of intermittent drug exposure. We assessed whether recurrent episodes of acute withdrawal contribute to the development of psychomotor sensitization in rodents during daily morphine exposure. The acoustic startle reflexFa measure of anxiety induced by opiate withdrawalFwas used to resolve and quantify discrete withdrawal episodes, and pharmacological interventions were used to manipulate withdrawal severity. Startle potentiation was observed during spontaneous withdrawal from a single morphine exposure, and individual differences in initial withdrawal severity positively predicted the subsequent development of sensitization. Manipulations that reduce or exacerbate withdrawal severity also produced parallel changes in the degree of sensitization. These results demonstrate that the episodic experience of withdrawal during daily drug exposure has a novel role in promoting the development of psychomotor sensitizationFa prominent model of drug-induced neurobehavioral plasticity. Episodic withdrawal may have a pervasive role in many effects of intermittent drug exposure and contribute to the development of addiction.

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“…At the level of the spinal cord, a key hub for the integration of pain signals, abrupt removal of μ-receptor agonists induces long-lasting synaptic facilitation within the superficial dorsal horn [8]. The interpretation that opioid withdrawal is a result of abnormal neuronal hyperexcitability led to the investigation of several therapeutic strategies, all with the intention to counteract opioid-induced hyperexcitability.…”

Section: Central Mechanisms Of Opioid Withdrawalmentioning

confidence: 99%

“…Several preclinical investigations have indicated that inhibitory transmission in key pain modulatory sites is compromised in animal models of morphine withdrawal. For instance, a reduction in inhibitory potassium channel currents was observed in the PAG [6] and activity of cAMP pathway was upregulated, resulting in increased glutamatergic tone in the rostroventral medulla [7].At the level of the spinal cord, a key hub for the integration of pain signals, abrupt removal of μ-receptor agonists induces long-lasting synaptic facilitation within the superficial dorsal horn [8]. The interpretation that opioid withdrawal is a result of abnormal neuronal hyperexcitability led to the investigation of several therapeutic strategies, all with the intention to counteract opioid-induced hyperexcitability.…”

mentioning

confidence: 99%

Therapies and Mechanisms of Opioid Withdrawal

2017

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Opioids are revered as potent analgesics, yet their clinical utility for managing pain is shrouded by concerns over the high abuse potential. With skyrocketing numbers of opioid prescriptions and off-label use, and a striking number of accidental opioid-related deaths and emergency room visits, North America has declared an 'opioid crisis'. In the USA alone, the number of prescribed opioids has quadrupled since 1999, with enough opioid prescriptions dispensed annually to provide a bottle for every household [1]. The opioid crisis, however, is not an isolated North American problem as virtually all developed countries have reported increased opioid consumption and deaths. The alarming rise in opioid-related deaths has stoked growing concerns about the safety of opioids, and increased reluctance on the part of some physicians to prescribe this class of drugs. This has created a conundrum: on one hand, opioids are essential for managing pain, but an over-reliance on opioids can put patients at risk of serious adverse effects, such as opioid analgesic tolerance (diminished pain-relieving effects), hyperalgesia (paradoxical increase in pain sensitivity) and drug dependence (manifesting as drug craving, seeking and/or physical withdrawal). The problem of opioid withdrawalAlthough adverse effects undermine the long-term clinical utility of opioids for pain management, terminating opioid therapy is also problematic because it can precipitate a debilitating withdrawal syndrome in chronic users. In this respect, opioid withdrawal is a significant challenge in patients where pain has resolved and there is no longer a need for opioid treatment, or those that are on dangerously high doses and a reduction in dose is prudent. Depending on the half-life of the opioid used, withdrawal typically presents between 8 and 48 h after the last opioid dose, with symptoms including gastrointestinal discomfort, anxiety, insomnia, muscle cramps and hyperhidrosis [2]. Individuals are therefore compelled to continue using opioids to avoid these unpleasant somatic, autonomic and emotional symptoms. Thus opioid withdrawal is a key determinant for continued opioid use and a contributing factor for relapse. A potential complication of terminating opioid therapy is the re-emergence of pain or exacerbation of a preexisting pain condition. Although pain is a major concern, patients on opioid therapy report that mitigation of withdrawal is a more important consideration for continued opioid use than pain management [3]. However, discerning between pain from a pre-existing condition and pain arising from opioid withdrawal is difficult. Patients may demand higher doses of opioids to manage a perceived worsening of pain, but the underlying reason may stem from withdrawal rather than a progression of a pre-existing pain condition. Withdrawal is also a key motivating factor for continued opioid use in off-label or nonprescription opioid users, and like prescription opioid users, many of these individuals may be better positioned to stop opioid use if mor...

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Induction of Synaptic Long-Term Potentiation After Opioid Withdrawal

Cited by 184 publications

References 27 publications

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Episodic Withdrawal Promotes Psychomotor Sensitization to Morphine

Therapies and Mechanisms of Opioid Withdrawal

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