Characterisation of the in vitro modulation of splenocyte proliferation by non-4,5-epoxymorphinan opioids

Hutchinson, Mark R.; Somogyi, Andrew A.

doi:10.1016/j.intimp.2005.05.006

Cited by 5 publications

(1 citation statement)

References 42 publications

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“…(+)-Methadone, which possesses no classical opioid receptor activity, causes significant glial activation, allodynia, and hyperalgesia, as well as up-regulation of proinflammatory cytokine mRNA, protein and release [21]. Other investigators have also demonstrated nonopioid morphine-induced hyperalgesia in triple opioid receptor knockout animals [52] and immunomodulation generally [53,54]. Glia do express classical opioid receptors [55].…”

Section: Opioids Simultaneously Induce Analgesia and Glial Activationmentioning

confidence: 99%

Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

Hutchinson

Bland

Johnson³

et al. 2007

The Scientific World JOURNAL

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311

282

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This review will introduce the concept of toll-like receptor (TLR)–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (˗)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use.

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Section: Opioids Simultaneously Induce Analgesia and Glial Activationmentioning

confidence: 99%

Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

Hutchinson

Bland

Johnson³

et al. 2007

The Scientific World JOURNAL

Self Cite

311

282

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Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids

Watkins¹,

Hutchinson²,

Ledeboer³

et al. 2007

Brain, Behavior, and Immunity

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303

232

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Within the past decade, there has been increasing recognition that glia are far more than simply "housekeepers" for neurons. This review explores two recently recognized roles of glia (microglia and astrocytes) in: (a) creating and maintaining enhanced pain states such as neuropathic pain, and (b) compromising the efficacy of morphine and other opioids for pain control. While glia have littleto-no role in pain under basal conditions, pain is amplified when glia become activated, inducing the release of proinflammatory products, especially proinflammatory cytokines. How glia are triggered to become activated is a key issue, and appears to involve a number of neuron-to-glia signals including neuronal chemokines, neurotransmitters, and substances released by damaged, dying and dead neurons. In addition, glia become increasingly activated in response to repeated administration of opioids. Products of activated glia increase neuronal excitability via numerous mechanisms, including direct receptor-mediated actions, upregulation of excitatory amino acid receptor function, downregulation of GABA receptor function, and so on. These downstream effects of glial activation amplify pain, suppress acute opioid analgesia, contribute to the apparent loss of opioid analgesia upon repeated opioid administration (tolerance), and contribute to the development of opioid dependence. The potential implications of such glial regulation of pain and opioid actions are vast, suggestive that targeting glia and their proinflammatory products may provide a novel and effective therapy for controlling clinical pain syndromes and increasing the clinical utility of analgesic drugs.

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“Listening” and “talking” to neurons: Implications of immune activation for pain control and increasing the efficacy of opioids

Watkins¹,

Hutchinson²,

Milligan³

et al. 2007

Brain Research Reviews

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162

135

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It is recently become clear that activated immune cells and immune-like glial cells can dramatically alter neuronal function. By increasing neuronal excitability, these non-neuronal cells are now implicated in the creation and maintenance of pathological pain, such as occurs in response to peripheral nerve injury. Such effects are exerted at multiple sites along the pain pathway, including at peripheral nerves, dorsal root ganglia, and spinal cord. In addition, activated glial cells are now recognized as disrupting the pain suppressive effects of opioid drugs and contributing to opioid tolerance and opioid dependence/withdrawal. While this review focuses on regulation of pain and opioid actions, such immune-neuronal interactions are broad in their implications. Such changes in neuronal function would be expected to occur wherever immune-derived substances come in close contact with neurons.

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Characterisation of the in vitro modulation of splenocyte proliferation by non-4,5-epoxymorphinan opioids

Cited by 5 publications

References 42 publications

Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids

“Listening” and “talking” to neurons: Implications of immune activation for pain control and increasing the efficacy of opioids

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