Toll-Like Receptor 4 Mutant and Null Mice Retain Morphine-Induced Tolerance, Hyperalgesia, and Physical Dependence

Mattioli, Theresa Alexandra; Leduc‐Pessah, Heather; Skelhorne‐Gross, Graham; Nicol, Christopher J.B.; Milne, Brian; Trang, Tuan; Cahill, Catherine M.

doi:10.1371/journal.pone.0097361

Cited by 78 publications

(63 citation statements)

References 49 publications

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“…Opioid-induced hyperalgesia was particularly evident in the sham rats, but was also clear after SCI on the measure of tactile reactivity. These data are commensurate with other animal 17,[68][69][70][71][72][73] and clinical studies demonstrating that both tolerance and hyperalgesia are commonly encountered among patients using opioids to control pain. 41,[74][75][76][77][78][79][80] While the behavioral effects of repeated opioid administration on hyperalgesia and tolerance are clear, the molecular changes that might mediate these effects are not.…”

supporting

confidence: 80%

Neurobiological Effects of Morphine after Spinal Cord Injury

Hook

Woller

Bancroft

et al. 2017

Journal of Neurotrauma

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Opioids and non-steroidal anti-inflammatory drugs are used commonly to manage pain in the early phase of spinal cord injury (SCI). Despite its analgesic efficacy, however, our studies suggest that intrathecal morphine undermines locomotor recovery and increases lesion size in a rodent model of SCI. Similarly, intravenous (IV) morphine attenuates locomotor recovery. The current study explores whether IV morphine also increases lesion size after a spinal contusion (T12) injury and quantifies the cell types that are affected by early opioid administration. Using an experimenter-administered escalating dose of IV morphine across the first seven days post-injury, we quantified the expression of neuron, astrocyte, and microglial markers at the injury site. SCI decreased NeuN expression relative to shams. In subjects with SCI treated with IV morphine, virtually no NeuN + cells remained across the rostral-caudal extent of the lesion. Further, whereas SCI per se increased the expression of astrocyte and microglial markers (glial fibrillary acidic protein and OX-42, respectively), morphine treatment decreased the expression of these markers. These cellular changes were accompanied by attenuation of locomotor recovery (Basso, Beattie, Bresnahan scores), decreased weight gain, and the development of opioid-induced hyperalgesia (increased tactile reactivity) in morphine-treated subjects. These data suggest that morphine use is contraindicated in the acute phase of a spinal injury. Faced with a lifetime of intractable pain, however, simply removing any effective analgesic for the management of SCI pain is not an ideal option. Instead, these data underscore the critical need for further understanding of the molecular pathways engaged by conventional medications within the pathophysiological context of an injury.

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confidence: 80%

Neurobiological Effects of Morphine after Spinal Cord Injury

Hook

Woller

Bancroft

et al. 2017

Journal of Neurotrauma

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“…Such effects of low dose antagonists also extend to the acute antinociception and tolerance produced by the spinal injections of the α 2 -adrenoceptor agonists clonidine or norepinephrine (Milne et al, 2011). These actions of the adrenoceptor antagonists on morphine-induced responses thus parallel the previously documented actions of ultra-low dose competitive opioid receptor antagonists, such as naltrexone (McNaull et al, 2007;Powell et al, 2002) and naloxone (Mattioli et al, 2014(Mattioli et al, , 2010. While the mechanisms underlying the crossover effects of the adrenergic antagonists on opioid agonistinduced responses remain unclear, they are not without precedence.…”

Section: Discussionsupporting

confidence: 58%

Analgesia, enhancement of spinal morphine antinociception, and inhibition of tolerance by ultra-low dose of the α2A-adrenoceptor selective antagonist BRL44408

Milne

Jhamandas

Sutak

et al. 2014

European Journal of Pharmacology

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Ultra-low doses of non-selective α2-adrenoceptor antagonists augment acute spinal morphine antinociception and block morphine tolerance; however, the receptor involved in mediating these effects is currently unknown. Here, we used tail flick and paw pressure tests on the rat to investigate the acute analgesic and tolerance-inducing effects of spinal morphine and norepinephrine alone or in combination with an ultra-low dose of the α2A-adrenoceptor antagonist, BRL44408. We also assessed the potential antinociceptive effects of BRL44408 alone following spinal administration. A spinal dose of BRL44408, over 1000-fold lower than that required to inhibit clonidine-induced antinociception (1.65ng/10µL), significantly prolonged morphine and norepinephrine action in both nociception tests. Following repeated morphine or norepinephrine injections, 1.65ng BRL44408 attenuated both the decline of antinociceptive effect and increase in morphine ED50 values, responses indicative of acute morphine tolerance. BRL44408 administered alone produced a delayed antinociceptive effect unrelated to repeated nociceptive testing. This response was partially reduced by the α2-adrenoceptor antagonist atipamezole (10µg). Ultra-low dose BRL44408 was able to inhibit the loss of morphine- and norepinephrine-induced antinociceptive response, and prevent the loss of drug potency due to repeated agonist exposure. This implicates the spinal α2A-adrenoceptor subtype in the action of ultra-low dose α2-adrenoceptor antagonists on morphine and norepinephrine tolerance. The BRL44408-induced analgesia is partially dependent on its interaction with the α2-adrenoceptors. Thus, this agent class may be useful in pain therapy.

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“…Maintenance of morphine-induced persistent sensitization is also dependent on this pathway, because inhibition of TLR4, P2X7R, caspase-1, or IL-1 reversed prolonged allodynia, an effect that was sustained after TLR4 or P2X7R antagonism. It should be noted that the role of TLR4 in OIH has been challenged (50,51), although these data do not preclude a role for this receptor in morphine-induced persistent sensitization. Furthermore, TLR4 is posited to exclusively regulate male pain behaviors (26,52).…”

Section: Discussionmentioning

confidence: 94%

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

Grace

Strand

Galer

et al. 2016

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

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Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-Noxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.

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Toll-Like Receptor 4 Mutant and Null Mice Retain Morphine-Induced Tolerance, Hyperalgesia, and Physical Dependence

Cited by 78 publications

References 49 publications

Neurobiological Effects of Morphine after Spinal Cord Injury

Neurobiological Effects of Morphine after Spinal Cord Injury

Analgesia, enhancement of spinal morphine antinociception, and inhibition of tolerance by ultra-low dose of the α2A-adrenoceptor selective antagonist BRL44408

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

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