RESUMEN
BACKGROUND: The anterior pretectal nucleus (APtN) activates descending mechanisms of pain control. This study evaluated whether the APtN also controls neuropathic pain in rats. METHODS: The hypersensitivity to mechanical stimulation with an electronic von Frey apparatus and the number of Fos-immunoreactive (Fos-ir) neurons in the APtN were evaluated in rats before and after chronic constriction injury of the sciatic nerve. RESULTS: The tactile hypersensitivity was characterized by an initial phase (the 2 days following the injury) and a maintenance phase (the subsequent 7 days). The injection of 2% lidocaine (0.25 µL) or N-methyl-D-aspartate (2.5 µg/0.25 µL) into the APtN intensified the tactile hypersensitivity observed 2 days after injury but did not alter the tactile hypersensitivity observed 7 and 14 days after injury. The injection of naloxone (10 ng/0.25 µL) or methysergide (40 pg/0.25 µL) but not atropine (100 ng/0.25 µL) into the APtN also intensified the tactile hypersensitivity observed 2 days after the injury. A significant increase in the number of Fos-ir cells was found in the contralateral APtN 2 days but not 7 or 14 days after the injury. Electrical stimulation of the APtN reduced the tactile hypersensitivity at 2, 7 and 14 days after the nerve ligation. CONCLUSION: APtN exerts a tonic inhibitory influence on persistent pain. The results point out to an important role of opioid and serotonergic mediation into the APtN to inhibit hyperalgesia during the initial phase of neuropathic pain.
Asunto(s)
Vías Nerviosas/patología , Neuralgia/patología , Área Pretectal/patología , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacología , Animales , Constricción Patológica/complicaciones , Constricción Patológica/patología , Hiperalgesia/fisiopatología , Lidocaína/administración & dosificación , Lidocaína/farmacología , Masculino , Metisergida/farmacología , N-Metilaspartato/administración & dosificación , N-Metilaspartato/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Neuronas/patología , Dimensión del Dolor/efectos de los fármacos , Estimulación Física , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Neuropatía Ciática/patologíaRESUMEN
A modification of the Bennett and Xie chronic constriction injury model of peripheral painful neuropathy was developed in rats. Under tribromoethanol anesthesia, a single ligature with 100% cotton glace thread was placed around the right sciatic nerve proximal to its trifurcation. The change in the hind paw reflex threshold after mechanical stimulation observed with this modified model was compared to the change in threshold observed in rats subjected to the Bennett and Xie or the Kim and Chung spinal ligation models. The mechanical threshold was measured with an automated electronic von Frey apparatus 0, 2, 7, and 14 days after surgery, and this threshold was compared to that measured in sham rats. All injury models produced significant hyperalgesia in the operated hind limb. The modified model produced mean ± SD thresholds in g (19.98 ± 3.08, 14.98 ± 1.86, and 13.80 ± 1.00 at 2, 7, and 14 days after surgery, respectively) similar to those obtained with the spinal ligation model (20.03 ± 1.99, 13.46 ± 2.55, and 12.46 ± 2.38 at 2, 7, and 14 days after surgery, respectively), but less variable when compared to the Bennett and Xie model (21.20 ± 8.06, 18.61 ± 7.69, and 18.76 ± 6.46 at 2, 7, and 14 days after surgery, respectively). The modified method required less surgical skill than the spinal nerve ligation model.
Asunto(s)
Umbral del Dolor/fisiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Nervio Ciático/lesiones , Animales , Modelos Animales de Enfermedad , Hiperalgesia/fisiopatología , Masculino , Dimensión del Dolor , Enfermedades del Sistema Nervioso Periférico/etiología , Ratas Wistar , Factores de TiempoRESUMEN
A modification of the Bennett and Xie chronic constriction injury model of peripheral painful neuropathy was developed in rats. Under tribromoethanol anesthesia, a single ligature with 100% cotton glace thread was placed around the right sciatic nerve proximal to its trifurcation. The change in the hind paw reflex threshold after mechanical stimulation observed with this modified model was compared to the change in threshold observed in rats subjected to the Bennett and Xie or the Kim and Chung spinal ligation models. The mechanical threshold was measured with an automated electronic von Frey apparatus 0, 2, 7, and 14 days after surgery, and this threshold was compared to that measured in sham rats. All injury models produced significant hyperalgesia in the operated hind limb. The modified model produced mean ± SD thresholds in g (19.98 ± 3.08, 14.98 ± 1.86, and 13.80 ± 1.00 at 2, 7, and 14 days after surgery, respectively) similar to those obtained with the spinal ligation model (20.03 ± 1.99, 13.46 ± 2.55, and 12.46 ± 2.38 at 2, 7, and 14 days after surgery, respectively), but less variable when compared to the Bennett and Xie model (21.20 ± 8.06, 18.61 ± 7.69, and 18.76 ± 6.46 at 2, 7, and 14 days after surgery, respectively). The modified method required less surgical skill than the spinal nerve ligation model.
Asunto(s)
Animales , Masculino , Umbral del Dolor/fisiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Nervio Ciático/lesiones , Modelos Animales de Enfermedad , Hiperalgesia/fisiopatología , Dimensión del Dolor , Enfermedades del Sistema Nervioso Periférico/etiología , Ratas Wistar , Factores de TiempoRESUMEN
Angiotensins (Angs) modulate blood pressure, hydro-electrolyte composition, and antinociception. Although Ang (5-8) has generally been considered to be inactive, we show here that Ang (5-8) was the smallest Ang to elicit dose-dependent responses and receptor-mediated antinociception in the rat ventrolateral periaqueductal gray matter (vlPAG). Ang (5-8) antinociception seems to be selective, because it did not alter blood pressure or act on vascular or intestinal smooth muscle cells. The non-selective Ang-receptor (Ang-R) antagonist saralasin blocked Ang (5-8) antinociception, but selective antagonists of Ang-R types I, II, IV, and Mas did not, suggesting that Ang (5-8) may act via an unknown receptor. Endopeptidase EP 24.11 and amastatin-sensitive aminopeptidase from the vlPAG catalyzed the synthesis (from Ang II or Ang III) and inactivation of Ang (5-8), respectively. Selective inhibitors of neuronal-nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and a non-selective opioid receptor (opioid-R) inhibitor blocked Ang (5-8)-induced antinociception. In conclusion, Ang (5-8) is a new member of the Ang family that selectively and strongly modulates antinociception via NO-sGC and endogenous opioid in the vlPAG.
Asunto(s)
Angiotensina I/farmacología , Guanilato Ciclasa/metabolismo , Óxido Nítrico/metabolismo , Nocicepción/efectos de los fármacos , Péptidos Opioides/metabolismo , Fragmentos de Péptidos/farmacología , Sustancia Gris Periacueductal/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/efectos de los fármacos , Antagonistas de Receptores de Angiotensina/farmacología , Animales , Aorta/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/fisiología , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Péptidos Opioides/antagonistas & inhibidores , Ratas , Ratas Wistar , Saralasina/farmacología , Guanilil Ciclasa Soluble , Teprotido/farmacologíaRESUMEN
AIMS: The purpose of this study was to examine whether the use of intraperitoneal or intrathecal amitriptyline combined with electroacupuncture modifies the tail-flick reflex and incision pain in rats that normally do not have analgesia to electroacupuncture in the tail-flick test (non-responder rats). MAIN METHODS: Changes in the nociceptive threshold of intraperitoneal or intrathecal saline- or amitriptyline-treated non-responder rats were evaluated using the tail-flick or incision pain tests before, during and after a 20-min period of electroacupuncture, applied at 2 Hz to the Zusanli and Sanynjiao acupoints. Amitriptyline was used at doses of 0.8 mg/kg or 30 µg/kg by intraperitoneal or intrathecal route, respectively. At these doses, amitriptyline has no effect against thermal or incision pain in rats. KEY FINDINGS: Rats selected as non-responders to the analgesic effect of electroacupuncture 2 Hz in tail-flick and incision pain tests become responders after an intraperitoneal or intrathecal injection of amitriptyline. SIGNIFICANCE: Amitriptyline converts non-responder rats to rats that respond to electroacupuncture with analgesia in a model of thermal phasic pain and anti-hyperalgesia in a model of incision pain.
Asunto(s)
Amitriptilina/uso terapéutico , Electroacupuntura , Dolor Nociceptivo/terapia , Umbral del Dolor/efectos de los fármacos , Analgésicos no Narcóticos/uso terapéutico , Animales , Terapia Combinada , Infusiones Parenterales , Inyecciones Espinales , Masculino , Ratas , Ratas WistarRESUMEN
AIM: This study examines if injection of cobalt chloride (CoCl(2)) or antagonists of muscarinic cholinergic (atropine), µ(1)-opioid (naloxonazine) or 5-HT(1) serotonergic (methiothepin) receptors into the dorsal or ventral portions of the anterior pretectal nucleus (APtN) alters the antinociceptive effects of stimulating the retrosplenial cortex (RSC) in rats. MAIN METHOD: Changes in the nociceptive threshold were evaluated using the tail flick or incision pain tests in rats that were electrically stimulated at the RSC after the injection of saline, CoCl(2) (1 mM, 0.10 µL) or antagonists into the dorsal or ventral APtN. KEY FINDINGS: The injection of CoCl(2), naloxonazine (5 µg/0.10 µL) or methiothepin (3 µg/0.10 µL) into the dorsal APtN reduced the stimulation-produced antinociception from the RSC in the rat tail flick test. Reduction of incision pain was observed following stimulation of the RSC after the injection of the same substances into the ventral APtN. The injection of atropine (10 ng/0.10 µL) or ketanserine (5 µg/0.10 µL) into the dorsal or ventral APtN was ineffective against the antinociception resulting from RSC stimulation. SIGNIFICANCE: µ(1)-opioid- and 5-HT(1)-expressing neurons and cell processes in dorsal and ventral APtN are both implicated in the mediation of stimulation-produced antinociception from the RSC in the rat tail flick and incision pain tests, respectively.
Asunto(s)
Corteza Cerebral/metabolismo , Terapia por Estimulación Eléctrica/métodos , Manejo del Dolor/métodos , Receptores Opioides mu/metabolismo , Receptores de Serotonina 5-HT1/metabolismo , Animales , Atropina/farmacología , Cobalto/farmacología , Modelos Animales de Enfermedad , Masculino , Metiotepina/farmacología , Naloxona/análogos & derivados , Naloxona/farmacología , Umbral del Dolor , Ratas , Ratas Wistar , Receptores Opioides mu/efectos de los fármacos , Receptores de Serotonina 5-HT1/efectos de los fármacosRESUMEN
The mechanisms through which electro-acupuncture (EA) and tricyclic antidepressants produce analgesia seem to be complementary: EA inhibits the transmission of noxious messages by activating supraspinal serotonergic and noradrenergic neurons that project to the spinal cord, whereas tricyclic antidepressants affect pain transmission by inhibiting the reuptake of norepinephrine and serotonin at the spinal level. This study utilized the tail-flick test and a model of post-incision pain to compare the antihyperalgesic effects of EA at frequencies of 2 or 100 Hz in rats treated with intraperitoneal or intrathecal amitriptyline (a tricyclic antidepressant). A gradual increase in the tail-flick latency (TFL) occurred during a 20-min period of EA. A strong and long-lasting reduction in post-incision hyperalgesia was observed after stimulation; the effect after 2 Hz lasting longer than after 100-Hz EA. Intraperitoneal or intrathecal amitriptyline potentiated the increase in TFL in the early moments of 2- or 100-Hz EA, and the intensity of the antihyperalgesic effect of 100-Hz EA in both the incised and non-incised paw. In contrast, it did not significantly change the intensity of the antihyperalgesic effect of 2-Hz EA. The EA-induced antihyperalgesic effects lasted longer after intraperitoneal or intrathecal amitriptyline than after saline, with this effect of amitriptyline being more evident after 100- than after 2-Hz EA. The synergetic effect of amitriptyline and EA against post-incision pain shown here may therefore represent an alternative for prolonging the efficacy of EA in the management of post-surgical clinical pain.
Asunto(s)
Amitriptilina/uso terapéutico , Analgésicos no Narcóticos/uso terapéutico , Electroacupuntura/métodos , Hiperalgesia/terapia , Manejo del Dolor/métodos , Amitriptilina/farmacología , Analgésicos no Narcóticos/farmacología , Animales , Terapia Combinada , Hiperalgesia/tratamiento farmacológico , Masculino , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Sympathetic ganglion block (SGB) or intravenous regional block (IVRB) has been recommended for pain management in patients with complex regional pain syndrome type I (CRPS-I). Forty-five patients were initially selected but only 43 were accepted for the study. The present study evaluated the efficacy of IVRB produced by combining 70 mg lidocaine with 30 µg clonidine (14 patients, 1 male/13 females, age range: 27-50 years) versus SGB produced by the injection of 70 mg lidocaine alone (14 patients, 1 male/13 females, age range: 27-54 years) or combined with 30 µg clonidine (15 patients, 1 male/14 females, age range: 25-50 years) into the stellate ganglion for pain management in patients with upper extremity CRPS-I. Each procedure was repeated five times at 7-day intervals, and pain intensity and duration were measured using a visual analog scale immediately before each procedure. A progressive and significant reduction in pain scores and a significant increase in the duration of analgesia were observed in all groups following the first three blocks, but no further improvement was obtained following the last two blocks. Drowsiness, the most frequent side effect, and dry mouth occurred only in patients submitted to SGB with lidocaine combined with clonidine. The three methods were similar regarding changes in pain intensity and duration of analgesia. However, IVRB seems to be preferable to SGB due to its easier execution and lower risk of undesirable effects.
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anestesia Intravenosa/métodos , Anestésicos Locales/administración & dosificación , Bloqueo Nervioso Autónomo/métodos , Clonidina/administración & dosificación , Lidocaína/administración & dosificación , Distrofia Simpática Refleja/tratamiento farmacológico , Anestésicos Locales/efectos adversos , Clonidina/efectos adversos , Ganglios Simpáticos , Lidocaína/efectos adversos , Dimensión del Dolor , Factores de Tiempo , Resultado del TratamientoRESUMEN
Sympathetic ganglion block (SGB) or intravenous regional block (IVRB) has been recommended for pain management in patients with complex regional pain syndrome type I (CRPS-I). Forty-five patients were initially selected but only 43 were accepted for the study. The present study evaluated the efficacy of IVRB produced by combining 70 mg lidocaine with 30 µg clonidine (14 patients, 1 male/13 females, age range: 27-50 years) versus SGB produced by the injection of 70 mg lidocaine alone (14 patients, 1 male/13 females, age range: 27-54 years) or combined with 30 µg clonidine (15 patients, 1 male/14 females, age range: 25-50 years) into the stellate ganglion for pain management in patients with upper extremity CRPS-I. Each procedure was repeated five times at 7-day intervals, and pain intensity and duration were measured using a visual analog scale immediately before each procedure. A progressive and significant reduction in pain scores and a significant increase in the duration of analgesia were observed in all groups following the first three blocks, but no further improvement was obtained following the last two blocks. Drowsiness, the most frequent side effect, and dry mouth occurred only in patients submitted to SGB with lidocaine combined with clonidine. The three methods were similar regarding changes in pain intensity and duration of analgesia. However, IVRB seems to be preferable to SGB due to its easier execution and lower risk of undesirable effects.
Asunto(s)
Anestesia Intravenosa/métodos , Anestésicos Locales/administración & dosificación , Bloqueo Nervioso Autónomo/métodos , Clonidina/administración & dosificación , Lidocaína/administración & dosificación , Distrofia Simpática Refleja/tratamiento farmacológico , Adulto , Anestésicos Locales/efectos adversos , Clonidina/efectos adversos , Femenino , Ganglios Simpáticos , Humanos , Lidocaína/efectos adversos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Factores de Tiempo , Resultado del TratamientoRESUMEN
Endogenous angiotensin (Ang) II and/or an Ang II-derived peptide, acting on Ang type 1 (AT(1)) and Ang type 2 (AT(2)) receptors, can carry out part of the nociceptive control modulated by periaqueductal gray matter (PAG). However, neither the identity of this putative Ang-peptide, nor its relationship to Ang II antinociceptive activity was clarified. Therefore, we have used tail-flick and incision allodynia models combined with an HPLC time course of Ang metabolism, to study the Ang III antinociceptive effect in the rat ventrolateral (vl) PAG using peptidase inhibitors and receptor antagonists. Ang III injection into the vlPAG increased tail-flick latency, which was fully blocked by Losartan and CGP 42,112A, but not by divalinal-Ang IV, indicating that Ang III effect was mediated by AT(1) and AT(2) receptors, but not by the AT(4) receptor. Ang III injected into the vlPAG reduced incision allodynia. Incubation of Ang II with punches of vlPAG homogenate formed Ang III, Ang (1-7) and Ang IV. Amastatin (AM) inhibited the formation of Ang III from Ang II by homogenate, and blocked the antinociceptive activity of Ang II injection into vlPAG, suggesting that aminopeptidase A (APA) formed Ang III from Ang II. Ang III can also be formed from Ang I by a vlPAG alternative pathway. Therefore, the present work shows, for the first time, that: (i) Ang III, acting on AT(1) and AT(2) receptors, can elicit vlPAG-mediated antinociception, (ii) the conversion of Ang II to Ang III in the vlPAG is required to elicit antinociception, and (iii) the antinociceptive activity of endogenous Ang II in vlPAG can be ascribed preponderantly to Ang III.
Asunto(s)
Analgésicos/farmacología , Angiotensina III/metabolismo , Nociceptores/efectos de los fármacos , Dolor/metabolismo , Sustancia Gris Periacueductal/metabolismo , Analgésicos/metabolismo , Angiotensina II/farmacología , Angiotensina III/farmacología , Antagonistas de Receptores de Angiotensina , Animales , Modelos Animales de Enfermedad , Interacciones Farmacológicas/fisiología , Vías Eferentes/efectos de los fármacos , Vías Eferentes/metabolismo , Glutamil Aminopeptidasa/biosíntesis , Losartán/farmacología , Masculino , Microinyecciones , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Nociceptores/metabolismo , Oligopéptidos/farmacología , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Péptidos/farmacología , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Angiotensina/metabolismoRESUMEN
1. Cholinergic agonists and acetylcholinesterase inhibitors, such as neostigmine, produce a muscarinic receptor-mediated antinociception in several animal species that depends on activation of spinal cholinergic neurons. However, neostigmine causes antinociception in sheep only in the early, and not late, postoperative period. 2. In the present study, a model of postoperative pain was used to determine the antinociceptive effects of bethanechol (a muscarinic agonist) and neostigmine administered intrathecally 2, 24 or 48 h after a plantar incision in a rat hind paw. Changes in the threshold to punctate mechanical stimuli were evaluated using an automated electronic von Frey apparatus. 3. Mechanical hyperalgesia was obtained following plantar incision, the effect being stronger during the immediate (2 h) than the late post-surgical period. Bethanechol (15-90 microg/5 microL) or neostigmine (1-3 microg/5 microL) reduced incision-induced mechanical hyperalgesia, the effects of both drugs being more intense during the immediate (2 h) than the late post-surgical period. 4. The ED(50) for bethanechol injected at 2, 24 and 48 h was 5.6, 51.9 and 82.5 microg/5 microL, respectively. The corresponding ED(50) for neostigmine was 1.62, 3.02 and 3.8 microg/5 microL, respectively. 5. The decline in the antinociceptive potency of neostigmine with postoperative time is interpreted as resulting from a reduction in pain-induced activation of acetylcholine-releasing descending pathways. However, the similar behaviour of bethanechol in the same model points to an additional mechanism involving intrinsic changes in spinal muscarinic receptors.
Asunto(s)
Analgesia/métodos , Betanecol/administración & dosificación , Neostigmina/administración & dosificación , Dolor Postoperatorio/tratamiento farmacológico , Animales , Inyecciones Espinales , Masculino , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Dolor Postoperatorio/etiología , Ratas , Ratas WistarRESUMEN
The amplification of pain long after the initial stimulus may be avoided if the treatment of pain is introduced before its initiation. However, conflicting evidence exists about the efficacy of such preemptive analgesia for the management of postoperative pain. This study compares the efficacy of intraplantar administration of indomethacin (a non-selective inhibitor of cyclooxygenase) and MK886 (an inhibitor of 5-lipoxygenase-activating protein), separately or in combination to produce preemptive analgesia in a model of surgical incisional pain in male Wistar rats. All incised rats (5 to 6 rats per group) had allodynia at 2, 6, and 24 h after surgery as evaluated using von Frey filaments. MK886, but not indomethacin (50 to 200 microg/paw), reduced the allodynia when injected either 1 h before or 1 h after surgery. The effect of preoperative MK886 (160 microg/paw) against incisional allodynia had a magnitude apparently similar to that produced by postoperative MK886. Pre-, but not postoperative MK886 (80 microg/paw) reduced the allodynia but the effect was seen only at 6 h after surgery. In contrast, MK886 (40 microg/paw) intensified the allodynia observed 2 h after the incision either injected before or after surgery. MK886 or indomethacin alone did not provide preemptive analgesia in the model of incisional pain. In contrast, the combination of MK886 with indomethacin reduced the allodynia more effectively when used before than after surgery, thus fulfilling the criteria for preemptive analgesia. In conclusion, preoperative inhibition of the local generation of both prostaglandins and leukotrienes by surgical incision may be an alternative to provide preemptive analgesia.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Indoles/administración & dosificación , Indometacina/administración & dosificación , Inhibidores de la Lipooxigenasa/administración & dosificación , Dolor Postoperatorio/prevención & control , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Masculino , Ratas , Ratas WistarRESUMEN
The amplification of pain long after the initial stimulus may be avoided if the treatment of pain is introduced before its initiation. However, conflicting evidence exists about the efficacy of such preemptive analgesia for the management of postoperative pain. This study compares the efficacy of intraplantar administration of indomethacin (a non-selective inhibitor of cyclooxygenase) and MK886 (an inhibitor of 5-lipoxygenase-activating protein), separately or in combination to produce preemptive analgesia in a model of surgical incisional pain in male Wistar rats. All incised rats (5 to 6 rats per group) had allodynia at 2, 6, and 24 h after surgery as evaluated using von Frey filaments. MK886, but not indomethacin (50 to 200 µg/paw), reduced the allodynia when injected either 1 h before or 1 h after surgery. The effect of preoperative MK886 (160 µg/paw) against incisional allodynia had a magnitude apparently similar to that produced by postoperative MK886. Pre-, but not postoperative MK886 (80 µg/paw) reduced the allodynia but the effect was seen only at 6 h after surgery. In contrast, MK886 (40 µg/paw) intensified the allodynia observed 2 h after the incision either injected before or after surgery. MK886 or indomethacin alone did not provide preemptive analgesia in the model of incisional pain. In contrast, the combination of MK886 with indomethacin reduced the allodynia more effectively when used before than after surgery, thus fulfilling the criteria for preemptive analgesia. In conclusion, preoperative inhibition of the local generation of both prostaglandins and leukotrienes by surgical incision may be an alternative to provide preemptive analgesia.
Asunto(s)
Animales , Masculino , Ratas , Antiinflamatorios no Esteroideos/administración & dosificación , Indoles/administración & dosificación , Indometacina/administración & dosificación , Inhibidores de la Lipooxigenasa/administración & dosificación , Dolor Postoperatorio/prevención & control , Modelos Animales de Enfermedad , Quimioterapia Combinada , Ratas WistarRESUMEN
Renin-angiotensin (Ang) system (RAS) peptides injected into the periaqueductal gray matter (PAG) elicit antinociception. Saralasin blocks Ang II-elicited antinociception. Thus, it is possible that endogenous RAS peptides could participate on the modulation of nociception in the PAG. This possibility was tested here injecting, in the PAG, the specific Ang type 1 and type 2 receptor (AT1 receptor and AT(2 receptor) antagonists losartan and CGP42,112A, respectively, either alone or before Ang II. The effects of Ang II, losartan and CGP42,112A on nociception were measured using the tail flick test and the model of incision allodynia. Ang II increased tail-flick latency, an effect inhibited by both losartan and CGP42,112A. Ang II reduced incisional allodynia. Either losartan or CGP42,112A alone increased incision allodynia, suggesting that endogenous Ang II and/or an Ang-peptide participates in the control of allodynia by the PAG. AT1 and AT2 receptors were immunolocalized in neuronal cell bodies and processes in the ventrolateral PAG. Taken together, the antinociceptive effect of Ang II injection into the ventrolateral PAG, the increase of allodynia elicited by injecting either losartan or CGP42,112A alone in the PAG, and the presence of AT1 and AT2 receptors in neurons and neuronal processes in the same region, represent the first evidence that part of the tonic nociceptive control mediated by the PAG is carried out locally by endogenous Ang II and/or an Ang-peptide acting on AT1 and AT2 receptors.
Asunto(s)
Nociceptores/fisiología , Sustancia Gris Periacueductal/fisiología , Receptores de Angiotensina/fisiología , Sistema Renina-Angiotensina/fisiología , Anestésicos Locales/farmacología , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Relación Dosis-Respuesta a Droga , Inmunohistoquímica/métodos , Lidocaína/farmacología , Losartán/farmacología , Masculino , Nociceptores/efectos de los fármacos , Oligopéptidos/farmacología , Dimensión del Dolor/métodos , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Receptores de Angiotensina/clasificación , Receptores de Angiotensina/efectos de los fármacos , Factores de TiempoRESUMEN
The anterior pretectal nucleus (APtN) participates in nociceptive processing and in the activation of central descending mechanisms of pain control. In this study we used behavioral tests (incisional pain and carrageenan-induced inflammatory pain) and c-Fos expression changes to examine the involvement of the APtN in the control of persistent pain in rats. A 1cm longitudinal incision through the skin and fascia of the plantar region (large incision), or a 0.5cm longitudinal incision through the skin only (small incision) was used, and the postoperative incisional allodynia was evaluated with von Frey filaments. The hyperalgesia produced by the intraplantar administration of carrageenan (25 or 50 microg/100 microl) into a hind paw was evaluated by a modified paw pressure test. The electrolytic lesion of the contralateral, but not ipsilateral, APtN significantly intensified the allodynia produced by a large incision of the hind paw. The incisional allodynia and the carrageenan-induced hyperalgesia were intensified by the microinjection of 2% lidocaine into the contralateral, but not ipsilateral APtN, the effect being significantly stronger when a large incision or a higher carrageenan concentration was utilized. A significant increase in the number of c-Fos positive cells was found in the ipsilateral, and mainly in the contralateral APtN of rats submitted to a large incision. The number of positive cells in the superficial or deep laminae of the contralateral spinal cord of control and incised rats was not significantly different. Positive cells in the superficial or deep laminae of the ipsilateral spinal cord were significantly more numerous than in control, the effect being significantly more intense in rats with large incision. The microinjection of 0.5% bupivacaine into the APtN contralateral to the incised hind paw reduced the number of positive cells bilaterally in the APtN, but the effect was significant in the contralateral nucleus only. The number of positive cells in the superficial and deep laminae of the contralateral spinal cord of incised and non-incised animals was not significantly changed by the neural block of the contralateral APtN. In the ipsilateral spinal cord, the incision-induced increase in the number of positive cells was significantly reduced in the superficial lamina and significantly increased in the deep lamina of animals previously treated with bupivacaine in the contralateral APtN. In conclusion, the integrity of the APtN is necessary to reduce the severity of the responses to persistent injury. The results also are in agreement with the current notion that persistent noxious inputs to the APtN tonically activate a descending mechanism that excites superficial cells and inhibits deep cells in the spinal dorsal horn.
Asunto(s)
Mesencéfalo , Dolor/metabolismo , Dolor/fisiopatología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Anestésicos Locales/administración & dosificación , Animales , Bupivacaína/farmacología , Carragenina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Lateralidad Funcional , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Inmunohistoquímica , Lidocaína/administración & dosificación , Masculino , Mesencéfalo/efectos de los fármacos , Microinyecciones/métodos , Dolor/inducido químicamente , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Wistar , Piel/lesiones , Piel/inervación , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patologíaRESUMEN
A close relationship exists between calcium concentration in the central nervous system and nociceptive processing. Aminoglycoside antibiotics and magnesium interact with N- and P/Q-type voltage-operated calcium channels. In the present study we compare the antinociceptive potency of intrathecal administration of aminoglycoside antibiotics and magnesium chloride in the tail-flick test and on incisional pain in rats, taken as models of phasic and persistent post-surgical pain, respectively. The order of potency in the tail-flick test was gentamicin (ED50 = 3.34 microg; confidence limits 2.65 and 4.2) > streptomycin (5.68 microg; 3.76 and 8.57) = neomycin (9.22 microg; 6.98 and 12.17) > magnesium (19.49 microg; 11.46 and 33.13). The order of potency to reduce incisional pain was gentamicin (ED50 = 2.06 microg; confidence limits 1.46 and 2.9) > streptomycin (47.86 microg; 26.3 and 87.1) = neomycin (83.17 microg; 51.6 and 133.9). The dose-response curves for each test did not deviate significantly from parallelism. We conclude that neomycin and streptomycin are more potent against phasic pain than against persistent pain, whereas gentamicin is equipotent against both types of pain. Magnesium was less potent than the antibiotics and effective in the tail-flick test only.
Asunto(s)
Analgésicos/farmacología , Antibacterianos/farmacología , Cloruro de Magnesio/farmacología , Dimensión del Dolor/efectos de los fármacos , Dolor/tratamiento farmacológico , Analgésicos/uso terapéutico , Animales , Antibacterianos/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Gentamicinas/farmacología , Inyecciones Espinales , Cloruro de Magnesio/uso terapéutico , Masculino , Neomicina/farmacología , Dolor/fisiopatología , Ratas , Ratas Wistar , Estreptomicina/farmacologíaRESUMEN
A close relationship exists between calcium concentration in the central nervous system and nociceptive processing. Aminoglycoside antibiotics and magnesium interact with N- and P/Q-type voltage-operated calcium channels. In the present study we compare the antinociceptive potency of intrathecal administration of aminoglycoside antibiotics and magnesium chloride in the tail-flick test and on incisional pain in rats, taken as models of phasic and persistent post-surgical pain, respectively. The order of potency in the tail-flick test was gentamicin (ED50 = 3.34 æg; confidence limits 2.65 and 4.2) > streptomycin (5.68 æg; 3.76 and 8.57) = neomycin (9.22 æg; 6.98 and 12.17) > magnesium (19.49 æg; 11.46 and 33.13). The order of potency to reduce incisional pain was gentamicin (ED50 = 2.06 æg; confidence limits 1.46 and 2.9) > streptomycin (47.86 æg; 26.3 and 87.1) = neomycin (83.17 æg; 51.6 and 133.9). The dose-response curves for each test did not deviate significantly from parallelism. We conclude that neomycin and streptomycin are more potent against phasic pain than against persistent pain, whereas gentamicin is equipotent against both types of pain. Magnesium was less potent than the antibiotics and effective in the tail-flick test only
Asunto(s)
Animales , Masculino , Ratas , Analgésicos , Antibacterianos , Cloruro de Magnesio , Dolor , Dimensión del Dolor , Antibacterianos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Gentamicinas , Inyecciones Espinales , Cloruro de Magnesio , Neomicina , Dolor , Ratas WistarRESUMEN
The treatment of pain before it initiates may prevent the persistent pain-induced changes in the central nervous system that amplify pain long after the initial stimulus. The effects of pre- or postoperative intraperitoneal administration of morphine (2 to 8 mg/kg), dipyrone (40 and 80 mg/kg), diclofenac (2 to 8 mg/kg), ketoprofen (10 and 20 mg/kg), and tenoxicam (10 and 20 mg/kg) were studied in a rat model of post-incisional pain. Groups of 5 to 8 male Wistar rats (140-160 g) were used to test each drug dose. An incision was made on the plantar surface of a hind paw and the changes in the withdrawal threshold to mechanical stimulation were evaluated with Von Frey filaments at 1, 2, 6 and 24 h after the surgery. Tenoxicam was given 12 or 6 h preoperatively, whereas the remaining drugs were given 2 h or 30 min preoperatively. Postoperative drugs were all given 5 min after surgery. No drug abolished allodynia when injected before or after surgery, but thresholds were significantly higher than in control during up to 2 h following ketoprofen, 6 h following diclofenac, and 24 h following morphine, dipyrone or tenoxicam when drugs were injected postoperatively. Significant differences between pre- and postoperative treatments were obtained only with ketoprofen administered 30 min before surgery. Preoperative (2 h) intraplantar, but not intrathecal, ketoprofen reduced the post-incisional pain for up to 24 h after surgery. It is concluded that stimuli generated in the inflamed tissue, rather than changes in the central nervous system are relevant for the persistence of pain in the model of post-incisional pain
Asunto(s)
Animales , Ratas , Masculino , Analgésicos Opioides/uso terapéutico , Antiinflamatorios no Esteroideos , Dolor Postoperatorio/tratamiento farmacológico , Mecanorreceptores , Piroxicam , Diclofenaco , Dipirona , Morfina , Umbral del Dolor , Estimulación Física , Piroxicam , Cuidados Posoperatorios , Cuidados Preoperatorios , Ratas WistarRESUMEN
The treatment of pain before it initiates may prevent the persistent pain-induced changes in the central nervous system that amplify pain long after the initial stimulus. The effects of pre- or postoperative intraperitoneal administration of morphine (2 to 8 mg/kg), dipyrone (40 and 80 mg/kg), diclofenac (2 to 8 mg/kg), ketoprofen (10 and 20 mg/kg), and tenoxicam (10 and 20 mg/kg) were studied in a rat model of post-incisional pain. Groups of 5 to 8 male Wistar rats (140-160 g) were used to test each drug dose. An incision was made on the plantar surface of a hind paw and the changes in the withdrawal threshold to mechanical stimulation were evaluated with Von Frey filaments at 1, 2, 6 and 24 h after the surgery. Tenoxicam was given 12 or 6 h preoperatively, whereas the remaining drugs were given 2 h or 30 min preoperatively. Postoperative drugs were all given 5 min after surgery. No drug abolished allodynia when injected before or after surgery, but thresholds were significantly higher than in control during up to 2 h following ketoprofen, 6 h following diclofenac, and 24 h following morphine, dipyrone or tenoxicam when drugs were injected postoperatively. Significant differences between pre- and postoperative treatments were obtained only with ketoprofen administered 30 min before surgery. Preoperative (2 h) intraplantar, but not intrathecal, ketoprofen reduced the post-incisional pain for up to 24 h after surgery. It is concluded that stimuli generated in the inflamed tissue, rather than changes in the central nervous system are relevant for the persistence of pain in the model of post-incisional pain.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Mecanorreceptores/efectos de los fármacos , Dolor Postoperatorio/tratamiento farmacológico , Piroxicam/análogos & derivados , Animales , Diclofenaco/uso terapéutico , Dipirona/uso terapéutico , Cetoprofeno/uso terapéutico , Masculino , Morfina/uso terapéutico , Umbral del Dolor , Estimulación Física , Piroxicam/uso terapéutico , Cuidados Posoperatorios , Cuidados Preoperatorios , Ratas , Ratas WistarRESUMEN
Calcium ions are widely recognized to play a fundamental role in the regulation of several biological processes. Transient changes in cytoplasmic calcium ion concentration represent a key step for neurotransmitter release and the modulation of cell membrane excitability. Evidence has accumulated for the involvement of calcium ions also in nociception and antinociception, including the analgesic effects produced by opioids. The combination of opioids with drugs able to interfere with calcium ion functions in neurons has been pointed out as a useful alternative for safer clinical pain management. Alternatively, drugs that reduce the flux of calcium ions into neurons have been indicated as analgesic alternatives to opioids. This article reviews the manners by which calcium ions penetrate cell membranes and the changes in these mechanisms caused by opioids and calcium antagonists regarding nociceptive and antinociceptive events.