RESUMO
Opioids are the "gold standard" treatment for postoperative pain, but these drugs also have limiting adverse effects. Thus, adjuvant drugs might be useful in opioid therapy for postoperative pain. The aim of the present study was to evaluate the effect of Phα1ß, a dual blocker of Cav2 and TRPA1 channels, on antinociceptive and adverse actions of morphine in a model of postoperative pain. Phα1ß (100-300 pmol/site) or morphine (3-10 mg/kg), alone, largely reduced postoperative nociception. However, Phα1ß (100 pmol/site) or morphine (10 mg/kg) also produced motor impairment. Lower doses of Phα1ß (30 pmol/site) or morphine (1 mg/kg), that did not have an effect alone, showed antinociceptive effect when concomitantly administrated. Moreover, co-administration of Phα1ß (30 pmol/site) with morphine (1 or 10 mg/kg) was unable to cause motor impairment. Preoperative repeated treatment with morphine increased the expression of Cav2 and TRPA1 channels in spinal cord, and caused tolerance and withdrawal syndrome, which were reversed with a single injection of Phα1ß (30 pmol/site). When injected postoperatively, escalating doses of morphine worsened postoperative hyperalgesia, induced tolerance, and withdrawal syndrome. Similarly, Phα1ß (30 pmol/site) reversed these adverse effects. Single or repeated morphine caused constipation, which was not altered by Phα1ß. Thus, a low dose of Phα1ß potentiated the analgesia, and reversed some adverse effects of morphine on operated mice, indicating the potential use of this agent as an adjuvant drug in opioid therapy for postoperative pain.
Assuntos
Analgésicos Opioides/uso terapêutico , Quimioterapia Adjuvante/métodos , Dor Pós-Operatória/tratamento farmacológico , Venenos de Aranha/uso terapêutico , Analgésicos , Animais , Canais de Cálcio Tipo N/metabolismo , Hiperalgesia/induzido quimicamente , Camundongos , Morfina , Venenos de Aranha/farmacologia , Canal de Cátion TRPA1/metabolismoRESUMO
BACKGROUND: Orofacial pain is clinically challenging, having therapeutic failures and side effects. This study evaluated the antinociceptive activities of the CTK 01512-2 toxin, the TRPA1 channel antagonist, and the selective inhibitor of the N-type voltage-gated calcium channels (N-type VGCC), in different pain models. MATERIALS AND METHODS: The trigeminal ganglia were stimulated in vitro with capsaicin. The in vivo models received subcutaneous (sc) injections of formalin into the upper lip of the rats, Freund's Complete Adjuvant (FCA) into the temporomandibular joint (TMJ), and infraorbital nerve constrictions (IONC). CTK 01512-2 at concentrations of 30, 100, and 300 pmol/site, intrathecally (ith), and MVIIA at 10, 30, and 100 pmol/site in the formalin test, guided the doses for the models. The glutamate levels in the CSF of the rats that were submitted to IONC were analyzed. RESULTS: CTK 01512-2 decreased the nociceptive behavior in the inflammatory phase of the formalin test (65.94 ± 7.35%) and MVIIA in the neurogenic phase (81.23 ± 3.36%). CTK 01512-2 reduced facial grooming with FCA in the TMJ (96.7 ± 1.6%), and in the IONC neuropathy model, it decreased heat hyperalgesia (100%) and cold hyperalgesia (81.61 ± 9.02%). The levels of glutamate in the trigeminal ganglia in vitro (81.40 ± 8.59%) and in the CSF in vivo (70.0 ± 9.2%) were reduced. CONCLUSIONS: The roles of TRPA1 in pain transduction and the performance of CTK 01512-2 in the inhibition of the N-type VGCCs were reinforced. This dual activity may represent an advantage in clinical treatments.
Assuntos
Analgésicos/farmacologia , Dor Facial/tratamento farmacológico , Canal de Cátion TRPA1/antagonistas & inibidores , ômega-Conotoxinas/farmacologia , Animais , Canais de Cálcio Tipo N/metabolismo , Capsaicina/farmacologia , Modelos Animais de Doenças , Adjuvante de Freund , Ácido Glutâmico/metabolismo , Hiperalgesia/tratamento farmacológico , Masculino , Neuralgia/tratamento farmacológico , Medição da Dor , Ratos , Ratos WistarRESUMO
UNLABELLED: Opioids are standard therapy for the treatment of pain; however, adverse effects limit their use. Voltage-gated calcium channel blockers may be used to increase opioid analgesia, but their effect on opioid-induced side effects is little known. Thus, the goal of this study was to evaluate the action of the peptide Phα1ß, a voltage-gated calcium channel blocker, on the antinociceptive and adverse effects produced by morphine in mice. A single administration of morphine (3-10 mg/kg) was able to reduce heat nociception as well as decrease gastrointestinal transit. The antinociception caused by a single injection of morphine was slightly increased by an intrathecal injection of Phα1ß (30 pmol/site). Repeated treatment with morphine caused tolerance, hyperalgesia, withdrawal syndrome, and constipation, and the Phα1ß (.1-30 pmol/site, intrathecal) was able to reverse these effects. Finally, the effects produced by the native form of Phα1ß were fully mimicked by a recombinant version of this peptide. Taken together, these data show that Phα1ß was effective in potentiating the analgesia caused by a single dose of morphine as well as in reducing tolerance and the adverse effects induced by repeated administration of morphine, indicating its potential use as an adjuvant drug in combination with opioids. PERSPECTIVE: This article presents preclinical evidence for a useful adjuvant drug in opioid treatment. Phα1ß, a peptide calcium channel blocker, could be used not only to potentiate morphine analgesia but also to reduce the adverse effects caused by repeated administration of morphine.
Assuntos
Analgésicos Opioides/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Morfina/uso terapêutico , Dor Nociceptiva/tratamento farmacológico , Peptídeos/uso terapêutico , Analgésicos Opioides/farmacologia , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Trânsito Gastrointestinal/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Naloxona , Antagonistas de Entorpecentes , Medição da Dor/efeitos dos fármacos , Peptídeos/farmacologiaRESUMO
Voltage-sensitive calcium channels (VSCCs) underlie cell excitability and are involved in the mechanisms that generate and maintain neuropathic and inflammatory pain. We evaluated in rats the effects of two VSCC blockers, ω-conotoxin MVIIA and Phα1ß, in models of inflammatory and neuropathic pain induced with complete Freund's adjuvant (CFA) and chronic constrictive injury (CCI), respectively. We also evaluated the effects of the toxins on capsaicin-induced Ca(2+) influx in dorsal root ganglion (DRG) neurons obtained from rats exposed to both models of pain. A single intrathecal injection of Phα1ß reversibly inhibits CFA and CCI-induced mechanical hyperalgesia longer than a single injection of ω-conotoxin MVIIA. Phα1ß and MVIIA also inhibited capsaicin-induced Ca(2+) influx in DRG neurons. The inhibitory effect of Phα1ß on capsaicin-induced calcium transients in DRG neurons was greater in the CFA model of pain, while the inhibitory effect of ω-conotoxin MVIIA was greater in the CCI model. The management of chronic inflammatory and neuropathic pain is still a major challenge for clinicians. Phα1ß, a reversible inhibitor of VSCCs with a preference for N-type Ca(2+) channels, has potential as a novel therapeutic agent for inflammatory and neuropathic pain. Clinical studies are necessary to establish the role of Phα1ß in the treatment of chronic pain.
Assuntos
Analgésicos/uso terapêutico , Modelos Animais de Doenças , Neuralgia/tratamento farmacológico , Neurotoxinas/uso terapêutico , Venenos de Aranha/uso terapêutico , Aranhas , ômega-Conotoxinas/uso terapêutico , Analgésicos/isolamento & purificação , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Neuralgia/patologia , Neurotoxinas/isolamento & purificação , Ratos , Ratos Wistar , Caramujos , Venenos de Aranha/isolamento & purificação , ômega-Conotoxinas/isolamento & purificaçãoRESUMO
Venoms peptides have produced exceptional sources for drug development to treat pain. In this study we examined the antinociceptive and side effects of Tx3-3, a peptide toxin isolated from Phoneutria nigriventer venom, which inhibits high-voltage-dependent calcium channels (VDCC), preferentially P/Q and R-type VDCC. We tested the effects of Tx3-3 in animal models of nociceptive (tail-flick test), neuropathic (partial sciatic nerve ligation and streptozotocin-induced diabetic neuropathy), and inflammatory (intraplantar complete Freund's adjuvant) pain. In the tail-flick test, both intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of Tx3-3 in mice caused a short-lasting effect (ED(50) and 95% confidence intervals of 8.8 [4.1-18.8] and 3.7 [1.6-8.4] pmol/site for i.t. and i.c.v. injection, respectively), without impairing motor functions, at least at doses 10-30 times higher than the effective dose. By comparison, ω-conotoxin MVIIC, a P/Q and N-type VDCC blocker derived from Conus magus venom, caused significant motor impairment at doses close to efficacious dose in tail flick test. Tx3-3 showed a long-lasting antinociceptive effect in neuropathic pain models. Intrathecal injection of Tx3-3 (30 pmol/site) decreased both mechanical allodynia produced by sciatic nerve injury in mice and streptozotocin-induced allodynia in mice and rats. On the other hand, i.t. injection of Tx3-3 did not alter inflammatory pain. Taken together, our data show that Tx3-3 shows prevalent antinociceptive effects in the neuropathic pain models and does not cause adverse motor effects at antinociceptive efficacious doses, suggesting that this peptide toxin holds promise as a novel therapeutic agent for the control of neuropathic pain. The Brazilian armed spider Tx3-3, a new P/Q and R-type calcium channel blocker, effectively alleviates allodynia in animal neuropathic pain models.
Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Neuropeptídeos/farmacologia , Neurotoxinas/farmacologia , Venenos de Aranha/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Neuralgia/etiologia , Neuralgia/patologia , Nociceptores/efeitos dos fármacos , Nociceptores/patologia , Ratos , Ratos WistarRESUMO
The transient potential vanilloid 1 receptor (TRPV1) is a calcium-permeable channel responsible for the transduction and modulation of acute and chronic pain signaling. As such, this receptor is a potential target for the treatment of a number of pain disorders. However, AMG517, a TRPV1 antagonist, presents several clinical limitations that include the induction of severe hyperthermia. The aim of this study was to investigate the possible interaction of the flavonoid eriodictyol with the TRPV1 receptor and to determine its putative antinociceptive and hyperthermic effects. Eriodictyol was able to displace [(3)H]-resiniferatoxin binding (IC(50)=47; 21-119nM) and to inhibit calcium influx mediated by capsaicin (IC(50)=44; 16-125nM), suggesting that eriodictyol acts as a TRPV1 antagonist. Moreover, eriodictyol induced antinociception in the intraplantar capsaicin test, with maximal inhibition of 49±10 and 64±4% for oral (ID(50)=2.3; 1.1-5.7mg/kg) and intrathecal (ID(50)=2.2; 1.7-2.9nmol/site) administration, respectively. Eriodictyol did not induce any change in body temperature or locomotor activity. Orally administered eriodictyol (4.5mg/kg) prevented the nociception induced by intrathecal injections of capsaicin, as well as the non-protein thiol loss and 3-nitrotyrosine (3-NT) formation induced by capsaicin in spinal cord. Eriodictyol also reduced the thermal hyperalgesia and mechanical allodynia elicited by complete Freund's adjuvant (CFA) paw injection. In conclusion, eriodictyol acts as an antagonist of the TRPV1 receptor and as an antioxidant; it induces antinociception without some of the side effects and limitations such as hyperthermia that are expected for TRPV1 antagonists.