Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar9,Met(O2)11]-substance P-saporin: Behavioral and anatomical analyses

Wiley, Ronald G.; Kline, R.; Vierck, Charles J.

doi:10.1016/j.neuroscience.2007.01.066

Cited by 55 publications

(49 citation statements)

References 35 publications

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“…The addition of [Sar 9 , Met(O 2 ) 11 ] to the substance P conjugated to saporin makes the agent more stable and potent than when substance P alone is bound to saporin. The dose and pre-treatment interval were based on the studies of Wiley and colleagues (Wiley et al, 2007) and Choi and colleagues (Choi et al, 2012), who observed no loss of intrinsic lumbar dorsal horn neurons expressing the neurokinin 1 (NK1) receptor in deeper laminae and prominent loss of NK1 receptor in laminae I, and others (Khasabov et al, 2002, Vierck et al, 2003, Weisshaar and Winkelstein, 2014, Kras et al, 2015, Araldi et al, 2016b). …”

Section: Methodsmentioning

confidence: 99%

Marked sexual dimorphism in 5-HT 1 receptors mediating pronociceptive effects of sumatriptan

et al. 2017

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Amongst the side effects of triptans, a substantial percentage of patients experience injection site pain and tenderness, the underlying mechanism of which is unknown. We found the dose range from 10 fg – 1000 ng (intradermal) sumatriptan induced a complex dose-dependent mechanical hyperalgesia in the male rat, with distinct peaks, at 1 pg and 10 ng, with no hyperalgesia at 1 ng. In female rats, there was 1 broad peak. The highest dose (1000 ng) did not produce hyperalgesia in either sex. We evaluated the receptors mediating sumatriptan hyperalgesia (1 pg, 1 and 10 ng). In male rats, while the injection of an antagonist for the serotonin (5-hydroxytryptamine, 5-HT) receptor subtype 1B (5-HT1B), but not 5-HT1D, markedly inhibited sumatriptan (1 pg hyperalgesia, at 10 ng a 5-HT1D receptor antagonist completely eliminated hyperalgesia. In contrast, in female rats, the 5-HT1D, but not 5-HT1B, receptor antagonist completely blocked sumatriptan (1 pg and 10 ng) hyperalgesia. Both 5-HT1B and 5-HT1D receptor antagonists attenuated hyperalgesia (1 ng) in females. Sumatriptan (1 ng)-induced hyperalgesia in female rats is G-protein-coupled estrogen receptor 30 dependent. While selective 5-HT1B, but not 5-HT1D, receptor agonists produces a robust hyperalgesia, when co-injected the hyperalgesia induced by 5-HT1B receptor agonist was attenuated. The mechanical hyperalgesia induced by sumatriptan (1 pg and 10 ng) is dependent on the Gi-protein α subunit and protein kinase A (PKA). Understanding the mechanisms responsible for the complex dose dependence for triptan hyperalgesia may provide useful information for the design of anti-migraine drugs with improved therapeutic profiles.

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Section: Methodsmentioning

confidence: 99%

Marked sexual dimorphism in 5-HT 1 receptors mediating pronociceptive effects of sumatriptan

et al. 2017

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“…As reported previously (Wiley et al, 2007), we used computer-assisted quantitative densitometry techniques to evaluate MOR1, MOR1C, and GIRK2 staining in the superficial dorsal horn. Using randomized coded sections to blind the operator to the experimental condition, user-defined areas of interest encompassing the entire mediolateral extent of laminas I and II were digitally captured using a Leica DM 6000B photomicroscope.…”

Section: Methodsmentioning

confidence: 99%

“…The Tukey's test was used for pairwise comparisons within the ANOVA analysis. The above procedures are similar to those described previously (Wiley et al, 2007). Linear regression analysis and product-moment correlation coefficients were calculated for analysis of interrelationships between variables, particularly doses of morphine versus hotplate behavior.…”

Section: Methodsmentioning

confidence: 99%

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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“…The new agent was seven times more potent than SPS and produced selective killing of NK-1R-expressing neurons in lamina I of the spinal cord without affecting deeper laminae. The behavioral effects of SSPS are similar to those of SPS, suggesting that the antinociceptive effects of both toxins are indeed due to selective loss of NK-1R neurons in lamina I [65]. The effects on nociception in animal models suggest that SPS-based molecules may be clinically useful in humans [63], however results of clinical trials have not been reported yet.…”

Section: Targeted Toxinsmentioning

confidence: 92%

“…Lumbar intrathecal injections of SPS destroy dorsal horn neurons that express the neurokinin-1 receptor (NK-1R) resulting in decreased responses to a range of noxious stimuli and decreased hyperalgesia and allodynia. Wiley et al performed in rats lumbar intrathecal injections of a more precisely targeted SPS conjugate, [Sar9,Met(O2)11]substance P-saporin (SSPS) [65]. The new agent was seven times more potent than SPS and produced selective killing of NK-1R-expressing neurons in lamina I of the spinal cord without affecting deeper laminae.…”

Section: Targeted Toxinsmentioning

confidence: 99%

Targeted biological therapies for pain

Rainov

Heidecke

2011

Expert Opinion on Biological Therapy

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Biological therapy of pain holds great promise and is rapidly developing. Despite the significant numbers of preclinical studies in the last two decades only a single biological agent, the cone snail toxin ziconotide, has been advanced through all stages and licensed for clinical use. Biological therapy of pain is thus here to stay, but will need more substantial proof of efficacy and safety before being widely accepted and routinely used.

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Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar9,Met(O2)11]-substance P-saporin: Behavioral and anatomical analyses

Cited by 55 publications

References 35 publications

Marked sexual dimorphism in 5-HT 1 receptors mediating pronociceptive effects of sumatriptan

Marked sexual dimorphism in 5-HT 1 receptors mediating pronociceptive effects of sumatriptan

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

Targeted biological therapies for pain

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