Involvement of enkephalins in the inhibition of osteosarcoma-induced thermal hyperalgesia evoked by the blockade of peripheral P2X3 receptors

González-Rodríguez, Sara; Pevida, Marta; Roques, Bernárd P.; Fournié‐Zaluski, Marie‐Claude; Hidalgo, Agustı́n; Menéndez, Luis; Baamonde, Ana

doi:10.1016/j.neulet.2009.09.015

Cited by 31 publications

(41 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The potentially effective 2a/gabapentin combination (Menendez et al 2008;Gonzalez-Rodriguez et al 2009) was thus assessed on mechanical allodynia in PSNL mice. Single oral administration of inactive doses of compound 2a (10 mg/kg) and gabapentin (30 mg/kg) 60 min before testing, did not produce any antiallodynic effect in nerveinjured mice when administered alone (Fig.…”

Section: Psnl-induced Neuropathic Pain In Micementioning

confidence: 99%

Long‐lasting oral analgesic effects of N‐protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain

Bonnard

Poras

Nadal

et al. 2015

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

The peripheral endogenous opioid system is critically involved in neuropathic and inflammatory pain generation as suggested by the modulation of opioid receptors expression and enkephalins (ENKs) release observed in these painful conditions. Accordingly, an innovative approach in the treatment of these nocifensive events is to increase and maintain high local concentrations of extracellular pain-evoked ENKs, by preventing their physiological enzymatic inactivation by two Zn metallopeptidases, the neutral endopeptidase (NEP, neprilysin, EC 3.4.24.11) and the neutral aminopeptidase (APN, EC 3.4.11.2). With this aim, new orally active dual ENKephalinase inhibitors (DENKIs) were designed as soluble prodrugs by introducing a N-terminal cleavable carbamate in the previously described aminophosphinic inhibitors. This induces long-lasting antinociceptive responses after oral administration, in various rodent models of inflammatory and neuropathic pain. These responses are mediated through stimulation of peripheral opioid receptors by DENKIs-protected ENKs as demonstrated by naloxone methiodide reversion. In all tested models, the most efficient prodrug 2a (PL265) was active, at least during 150–180 min, after single oral administration of 25–50 mg/kg in mice and of 100–200 mg/kg in rats. In models of neuropathic pain, both hyperalgesia and allodynia were markedly reduced. Interestingly, combination of inactive doses of 2a (PL265) and of the anti-epileptic drug gabapentin had synergistic effect on neuropathic pain. Pharmacokinetic studies of 2a (PL265) in rats show that the active drug is the only generated metabolite produced. These encouraging results have made 2a (PL265) a suitable candidate for clinical development.

show abstract

Section: Psnl-induced Neuropathic Pain In Micementioning

confidence: 99%

Long‐lasting oral analgesic effects of N‐protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain

Bonnard

Poras

Nadal

et al. 2015

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

show abstract

“…The competitive antagonist A-317491 blocks both P2X3 and P2X2/3 receptors [73] and was shown to attenuate pain-related behaviors in two different murine models and a rat model of cancer-induced bone pain [68–70]. González-Rodríguez et al showed that A-317491 injected subcutaneously over a tibial tumor mass dose-dependently inhibited tumor-induced thermal hyperalgesia in the affected limb but not in the nontumor bearing limb.…”

Section: P2x Receptors At the Peripheral Site In Relation To Cancementioning

confidence: 99%

“…González-Rodríguez et al showed that A-317491 injected subcutaneously over a tibial tumor mass dose-dependently inhibited tumor-induced thermal hyperalgesia in the affected limb but not in the nontumor bearing limb. Interestingly, coadministration of an anti-met-enkephalin antibody abolished the antihyperalgesic effect of A-317491 suggesting that in this model the effect of A-317491 occurs through stimulation of peripheral opioid receptors [68]. The involvement of endogenous opioid mechanisms in P2X3 and P2X2/3 receptor-related antinociception has also been described in rat models of inflammatory pain [74].…”

Section: P2x Receptors At the Peripheral Site In Relation To Cancementioning

confidence: 99%

The Role of Purinergic Receptors in Cancer-Induced Bone Pain

Falk

Uldall

Heegaard

2012

Journal of Osteoporosis

View full text Add to dashboard Cite

Cancer-induced bone pain severely compromises the quality of life of many patients suffering from bone metastasis, as current therapies leave some patients with inadequate pain relief. The recent development of specific animal models has increased the understanding of the molecular and cellular mechanisms underlying cancer-induced bone pain including the involvement of ATP and the purinergic receptors in the progression of the pain state. In nociception, ATP acts as an extracellular messenger to transmit sensory information both at the peripheral site of tissue damage and in the spinal cord. Several of the purinergic receptors have been shown to be important for the development and maintenance of neuropathic and inflammatory pain, and studies have demonstrated the importance of both peripheral and central mechanisms. We here provide an overview of the current literature on the role of purinergic receptors in cancer-induced bone pain with emphasis on some of the difficulties related to studying this complex pain state.

show abstract

“…P2X 3 expression (both protein and mRNA) in DRG neurons is upregulated following chronic constriction injury (CCI) of the sciatic nerve (Novakovic et al, ), whereas sensitization and nociceptive symptoms of ATP are reduced through P2X 3 receptor antagonists (Gonzalez‐Rodriguez et al, ). This implies that the P2X 3 receptor should be considered as a therapeutic target in the treatment of neuropathic pain (Kennedy et al, ).…”

mentioning

confidence: 99%

“…A key role for the P2X 3 receptor subunit in transmitting signals of chronic inflammatory and neuropathic pain has been indicated through experiments that used receptor agonists and antagonists (Jacobson et al, 2006), antisense oligonucleotides , and gene knockouts (Souslova et al, 2000;Jiang et al, 2003). P2X 3 expression (both protein and mRNA) in DRG neurons is upregulated following chronic constriction injury (CCI) of the sciatic nerve (Novakovic et al, 1999), whereas sensitization and nociceptive symptoms of ATP are reduced through P2X 3 receptor antagonists (Gonzalez-Rodriguez et al, 2009). This implies that the P2X 3 receptor should be considered as a therapeutic target in the treatment of neuropathic pain (Kennedy et al, 2003).…”

mentioning

confidence: 99%

Electroacupuncture and A‐317491 depress the transmission of pain on primary afferent mediated by the P2X₃ receptor in rats with chronic neuropathic pain states

Wang

Cheng

et al. 2014

J of Neuroscience Research

View full text Add to dashboard Cite

P2X is a family of ligand-gated ion channels that act through adenosine ATP. The P2X3 receptor plays a key role in the transmission of neuropathic pain at peripheral and spinal sites. Electroacupuncture (EA) has been used to treat neuropathic pain effectively. To determine the role of EA in neuropathic pain mediated through the P2X3 receptor in dorsal root ganglion neurons and the spinal cord, a chronic constriction injury (CCI) model was used. Sprague-Dawley rats were divided into four groups: sham CCI, CCI, CCI plus contralateral EA, and CCI plus ipsilateral EA. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded. Furthermore, the expression of the P2X3 receptor was evaluated through Western blotting and immunofluorescence. The effects of EA and A-317491 were investigated through the whole-cell patch-clamp method and intrathecal administration. Our results show that the MWT and TWL of EA groups were higher than those in the CCI group, whereas the expression of the P2X3 receptor was lower than that in the CCI group. However, no significant difference was detected between the two EA groups. EA depressed the currents created by ATP and the upregulation of the P2X3 receptor in CCI rats. Additionally, EA was more potent in reducing mechanical allodynia and thermal hyperalgesia when combined with A-317491 through intrathecal administration. These results show that both contralateral and ipsilateral EA might inhibit the primary afferent transmission of neuropathic pain induced through the P2X3 receptor. In addition, EA and A-317491 might have an additive effect in inhibiting the transmission of pain mediated by the P2X3 receptor.

show abstract

Involvement of enkephalins in the inhibition of osteosarcoma-induced thermal hyperalgesia evoked by the blockade of peripheral P2X3 receptors

Cited by 31 publications

References 24 publications

Long‐lasting oral analgesic effects of N‐protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain

Long‐lasting oral analgesic effects of N‐protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain

The Role of Purinergic Receptors in Cancer-Induced Bone Pain

Electroacupuncture and A‐317491 depress the transmission of pain on primary afferent mediated by the P2X₃ receptor in rats with chronic neuropathic pain states

Contact Info

Product

Resources

About

Involvement of enkephalins in the inhibition of osteosarcoma-induced thermal hyperalgesia evoked by the blockade of peripheral P2X3 receptors

Cited by 31 publications

References 24 publications

Long‐lasting oral analgesic effects of N‐protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain

Long‐lasting oral analgesic effects of N‐protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain

The Role of Purinergic Receptors in Cancer-Induced Bone Pain

Electroacupuncture and A‐317491 depress the transmission of pain on primary afferent mediated by the P2X3 receptor in rats with chronic neuropathic pain states

Contact Info

Product

Resources

About

Electroacupuncture and A‐317491 depress the transmission of pain on primary afferent mediated by the P2X₃ receptor in rats with chronic neuropathic pain states