Systemic and supraspinal, but not spinal, opiates suppress allodynia in a rat neuropathic pain model

Lee, Youn-Woo; Chaplan, Sandra R.; Yaksh, Tony L.

doi:10.1016/0304-3940(95)12034-2

Cited by 165 publications

(83 citation statements)

References 13 publications

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“…The ICV route for drug injection was constructed through skull (11). Placing the rat in a stereotactic holder under enflurane (3-4%)/O2 anesthesia, a burr hole was made at 0.5 mm caudally from the coronal suture and 1.0 mm laterally from the sagittal suture.…”

Section: Methodsmentioning

confidence: 99%

Hemodynamic Effects of Gabapentin in Rats

Yoon

Choi

2003

J Korean Med Sci

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Gabapentin has been known to elicit the antinociceptive effect. However, little has been known about the effect of gabapentin on the cardiovascular system. The author's aim of this experiment was to examine the hemodynamic effects of gabapentin. Male Sprague-Dawley rats were used. Intrathecal or intracerebroventricular catheters were implanted and gabapentin was delivered through each catheter or directly into the peritoneal cavity. For hemodynamic measurements, catheters were inserted into the tail artery. Blood pressure and heart rate were measured over 60 min following administration of gabapentin. Intrathecal and intraperitoneal gabapentin did not induce significant changes of hemodynamics over the 60 min compared to the baseline value. Intracerebroventricular gabapentin increased systolic and diastolic blood pressure, but there is no statistically difference in blood pressure change according to the dose.

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Section: Methodsmentioning

confidence: 99%

Hemodynamic Effects of Gabapentin in Rats

Yoon

Choi

2003

J Korean Med Sci

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“…Differential nerve blocks applied to patients demonstrated that allodynia is mediated through non-nociceptive, large diameter Aβ fibers whereas thermal hyperalgesia is mediated through the unmyelinated C-fiber nociceptors (Campbell et al 1988;Koltzenburg et al 1992;Koltzenburg et al 1994). Selective desensitization of Cfibers or presynaptic inhibition of C-fiber output with spinal morphine abolished thermal, but not tactile, hyperesthesias in rats with spinal nerve ligation (SNL) (Bian et al 1995;Lee et al 1995;Ossipov et al 1999). Likewise, inhibition of C-fiber activity did not alter behavioral responses to light brush in nerve-injured rats (Field et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Nerve injury-induced tactile allodynia is present in the absence of FOS labeling in retrogradely labeled post-synaptic dorsal column neurons

Zhang

Ossipov

Zhang

et al. 2007

Pain

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The dorsal column pathway consists of direct projections from primary afferents and of ascending fibers of the post-synaptic dorsal column (PSDC) cells. This pathway mediates touch but may also mediate allodynia after nerve injury. The role of PSDC neurons in nerve injury-induced mechanical allodynia is unknown. Repetitive gentle, tactile stimulus or noxious pinch was applied to the ipsilateral hindpaw of rats with spinal nerve ligation (SNL) or sham surgery that had previously received tetramethylrhodamine dextran in the ipsilateral n. gracilis. Both touch and noxious stimuli produced marked increases in FOS expression in other cells throughout all laminae of the ipsilateral dorsal horn after nerve injury. However, virtually none of the identified PSDC cells expressed FOS immunofluorescence in response to repetitive touch or pinch in either the nerve-injured or sham groups. In contrast, labeled PSDC cells expressed FOS in response to ureter ligation and labeled spinothalamic tract (STT) cells expressed FOS in response to noxious pinch. Identified PSDC neurons from either sham-operated or SNL rats did not express immunoreactivity to substance P, CGRP, NPY, PKCg, MOR, the NK1 and the NPY-Y1 receptor. Retrogradely labeled DRG cells of nerve injured rats were large diameter neurons, which expressed NPY, but no detectable CGRP or substance P. Spinal nerve injury sensitizes neurons in the spinal dorsal horn to repetitive light touch but PSDC neurons apparently do not participate in touch-evoked allodynia. Sensitization of these non-PSDC neurons may result in activation of projections integral to the spinal/supraspinal processing of enhanced pain states and of descending facilitation, thus priming the central nervous system to interpret tactile stimuli as being aversive.

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“…Subsequent signaling leads to decreased cyclic adenosine monophosphate (AMP) and hyperpolarization due to reduced calcium influx and increased potassium efflux, blocking pain transmission. 24,41,42,45,[47][48][49]58 Chronic opioid use has been shown paradoxically to cause excitatory rather than inhibi tory effects on the cell, stimulating pain propagation. 11,14,26,27,31,40,67,76 This enhanced pain and the underlying excitatory signaling have been proposed to be mediated by opioid receptors preferentially coupling to G s proteins, 19,60 or alternatively, via the Gβγ dimer of the G i/o proteins native to opioid receptors.…”

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confidence: 99%

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

Largent-Milnes

Guo

Wang

et al. 2008

The Journal of Pain

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Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)-G protein coupling from G i/o to G s that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L 5 /L 6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G s in the damaged (ipsilateral) spinal dorsal horn. This MOR-G s coupling occurred without changing G i/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G s coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G s coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G s coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G s coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. KeywordsNeuropathic pain; G protein coupling; tolerance; opioids; hyperalgesia; allodynia; μ-opioid receptor Patients who have diseases such as cancer, arthritis, and diabetes often have development of painful neuropathies due to disease progression or medical treatment. HHS Public AccessAuthor manuscript J Pain. Author manuscript; available in PMC 2017 June 13. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript approaches used in the clinic to treat these neuropathies include tricyclic antidepressants, dual-acting reuptake inhibitors, and anticonvulsants (eg, gabapentin) or combinations of these with nonsteroidal anti-flammatory drugs (NSAIDs) and opioids. However, these options often cause side effects such as dizziness and sedation and may not treat the various classifications of neuropathic pain states with comparable efficacy. 30,32,55,77 Treatment of neuropathic pain that is not responsive to first-line therapies is often limited to opioids, which can be effective acutely but have decreased efficacy after chronic exposure, leading to the use of higher doses to achieve the same level of pain relief and often resulting in opioidinduced mechanical and thermal hypersensitivities. 5,7,9,29,30,32,[69][70][71]79,81 For patients taking higher doses of opioids to achieve pain relief, the presence of unwanted side effects including tolerance, dependence, respiratory depression, and constipation furthe...

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Systemic and supraspinal, but not spinal, opiates suppress allodynia in a rat neuropathic pain model

Cited by 165 publications

References 13 publications

Hemodynamic Effects of Gabapentin in Rats

Hemodynamic Effects of Gabapentin in Rats

Nerve injury-induced tactile allodynia is present in the absence of FOS labeling in retrogradely labeled post-synaptic dorsal column neurons

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

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