RESUMEN
Objective: To perform lymphocyte micronucleus analysis on radiation workers with long-term exposure to low doses ionizing radiation, Evaluate the health condition of radiation workers, and provide the evidence for strengthening surveillance of radiation workers. Methods: From January 1, 2013 to December 21, 2016, a statistical analysis and evaluation was conducted of the peripheral lymphocytes micronucleus rate in 5 901 radiation workers who had undergone medical examinations of employees at Chinese Academy of Medical Sciences Institute of Radiation Medicine. Results: The micronucleus rates in radiation workers of the on-job group were higher than the pre-job group (P<0.01) . Significant difference was found among the different sex (t=5.97) , different types (χ(2)=378.69) , different levels of work units (χ(2)=115.48) . Significant difference was found among the micronucleus rates of 672 radiation workers of the on-job group from 2013 to 2016 (χ(2)=92.57, P<0.01) . Conclusion: The peripheral lymphocytes micronucleus rate of radiation workers were significantly higher than non-contact workers. Significant increasing trend of micronucleus rates was noted among the radiation worker with increasing exposure time. The peripheral lymphocytes micronucleus rates of interventional therapy workers were highest. The peripheral lymphocytes micronucleus rates of Private hospitals workers were highest. This phenomenon deserves attention. Protection needs to be strengthened to ensure the health of radiation workers.
Asunto(s)
Núcleo Celular/efectos de la radiación , Pruebas de Micronúcleos/métodos , Enfermedades Profesionales , Exposición Profesional/efectos adversos , Radiación Ionizante , Radiología , Pueblo Asiatico/genética , Relación Dosis-Respuesta en la Radiación , Humanos , Linfocitos , Recursos HumanosRESUMEN
Here we studied the role of peripheral adenosine A(2A) receptors in mechanical hyperalgesia during inflammation using mice lacking the A(2A) receptors. Unilateral s.c. administration of the local inflammatory agent λ-carrageenan induced profound mechanical hyperalgesia 24 h after administration in the ipsilateral hind paw in wild-type mice. In homozygous mice lacking the A(2A) receptors, carrageenan-induced hyperalgesia was significantly reduced compared to wild type controls. The reduction in inflammatory hyperalgesia seen in A(2A) receptor knock-out mice was not associated with changes in paw edema. CGS 21680, a selective A(2A) receptor agonist, produced significantly more mechanical hyperalgesia in wild type females than in wild type males upon direct s.c. injection into the hindpaw whereas it had no effect upon systemic administration. The hyperalgesic effect of CGS 21680 was markedly reduced in the A(2A) knock-out mice of both sexes. Subcutaneous ZM-241,385, a selective A(2A) receptor antagonist, injected into the hindpaw reduced the mechanical hyperalgesia following carrageenan in female mice, but not in males. The results indicate that activation of peripheral adenosine A(2A) receptors during inflammation is associated with mechanical hyperalgesia, and that this effect is more prominent in females than in males.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Hiperalgesia/fisiopatología , Receptor de Adenosina A2A/fisiología , Adenosina/administración & dosificación , Adenosina/análogos & derivados , Adenosina/farmacología , Agonistas del Receptor de Adenosina A2/administración & dosificación , Agonistas del Receptor de Adenosina A2/farmacología , Animales , Carragenina , Femenino , Ganglios Espinales/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/complicaciones , Hiperalgesia/genética , Inflamación/inducido químicamente , Inflamación/complicaciones , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Noqueados , Dolor , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Fenetilaminas/administración & dosificación , Fenetilaminas/farmacología , Receptor de Adenosina A2A/genética , Receptor de Adenosina A2A/metabolismo , Caracteres Sexuales , Triazinas/farmacología , Triazoles/farmacologíaRESUMEN
The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. The effect of galanin is mediated by at least three subtypes of receptors. In the present study, we assessed the nociceptive sensitivity in mice lacking the galanin receptor 1 gene (Galr1) and the development of neuropathic pain-like behaviours after photochemically induced partial sciatic nerve ischaemic injury. Under basal condition, Galr1 knock-out (Galr1(-/-)) mice had shortened response latency on the hot plate, but not tail flick and paw radiant heat, tests. The mechanical sensitivity was not different between Galr1(-/-) and wild type (Galr1(+/+)) mice, whereas the cold response was moderately enhanced in Galr1(-/-) mice. Both Galr1(-/-) mice and Galr1(+/+) controls developed mechanical and heat hypersensitivity after partial sciatic nerve injury. The duration of such pain-like behaviours was significantly increased in Galr1(-/-). The Galr1(-/-) mice and Galr1(+/+) mice did not differ in their recovery from deficits in toe-spread after sciatic nerve crush. The results provide some evidence for an inhibitory function for the neuropeptide galanin acting on galanin receptor 1 (GALR1) in nociception and neuropathic pain after peripheral nerve injury in mice.
Asunto(s)
Hiperalgesia/metabolismo , Umbral del Dolor/fisiología , Receptores de Neuropéptido/biosíntesis , Receptores de Neuropéptido/deficiencia , Animales , Frío , Calor , Hiperalgesia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dimensión del Dolor/métodos , Receptores de Galanina , Receptores de Neuropéptido/genética , Neuropatía Ciática/metabolismoRESUMEN
Mice with a targeted disruption of adenosine A(3) receptor (A(3)AR) gene were assessed for their nociceptive threshold and for their localized inflammatory response following carrageenan injected into the hindpaw. Under basal conditions no difference was seen between A(3)AR knock-out (A(3)AR(-/-)) and wild-type (A(3)AR(+/+)) mice in nociceptive response to mechanical or heat stimuli. The antinociceptive response to the intrathecal adenosine analogue R-phenylisopropyl adenosine (R-PIA) was also unchanged in the A(3)AR(-/-) mice. In contrast, heat hyperalgesia, plasma extravasation and edema following carrageenan-induced inflammation in the hind paw were significantly reduced in A(3)AR(-/-) mice compared to the A(3)AR(+/+) controls. Thus, mice lacking A(3)AR had deficits in generating the localized inflammatory response to carrageenan, supporting a pro-inflammatory role of A(3)AR in peripheral tissues. However, no evidence for a role of A(3)AR in nociception and the antinociceptive effect of R-PIA was found.
Asunto(s)
Carragenina/efectos adversos , Umbral del Dolor/fisiología , Dolor/patología , Receptores Purinérgicos P1/deficiencia , Animales , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dolor/inducido químicamente , Dolor/genética , Dolor/metabolismo , Dimensión del Dolor/métodos , Receptor de Adenosina A3 , Receptores Purinérgicos P1/genéticaRESUMEN
Cholecystokinin (CCK) is a physiological antagonist of opioid-mediated antinociception and may be involved in some chronic pain states where opioids have reduced effect. We have previously shown in a rat model of central neuropathic pain after spinal cord injury that blockade of CCK-B receptors lead to marked pain relief. In the present study, we showed that spinally injured rats exhibiting chronic pain-like behaviors (aversive reaction to innocuous mechanical and cold stimulation) had significantly elevated level of CCK-like immunoreactivity in cerebrospinal fluid compared to normal rats or spinally injured rats which did not exhibit pain-like behaviors. The increased level of circulating CCK in the cerebrospinal fluid may thus contribute to the maintenance of chronic pain in these rats by reducing the endogenous inhibitory tone provided by opioid peptides and may be involved in the phenomenon of opioid insensitivity.
Asunto(s)
Conducta Animal , Colecistoquinina/biosíntesis , Colecistoquinina/líquido cefalorraquídeo , Dolor , Traumatismos de la Médula Espinal/metabolismo , Animales , Femenino , Inmunoglobulina G/metabolismo , Narcóticos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Colecistoquinina B , Receptores de Colecistoquinina/metabolismoRESUMEN
The present study assessed the efficacy and potency of intrathecal (i.t.) administration of the opiate morphine, the gamma-aminobutyric acid-B (GABA(B)) receptor agonist baclofen, the alpha2-adrenoceptor agonist clonidine and the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) on the acute allodynia-like behaviour after photochemically induced spinal cord injury (SCI) in rats. Rats displaying allodynia-like behaviours to brushing, von Frey hairs and cold stimulation 1-2 days after photochemically induced SCI were studied. In a cumulative dose regime, morphine (0.1-10 micrcog), baclofen (0.1-1 microg), clonidine (0.1-10 microg) and R-PIA (0.01-10 nmol) were administered i.t. through an implanted catheter at the lumbar spinal cord. All tested drugs dose-dependently reduced the brushing, von Frey hairs and cold stimulation-induced allodynia-like behaviour. No increase in adverse effects such as motor deficits was found for morphine, clonidine and R-PIA. There was a slight increase in motor impairments at the highest dose of baclofen. For the mechanical allodynia, morphine appeared to be most effective, whereas baclofen, clonidine and R-PIA only provided a partial alleviation. For the cold allodynia, morphine and baclofen were more effective than clonidine and R-PIA. In relieving acute mechanical and cold allodynia-like behaviours in rats 1-2 days after SCI, i.t. morphine and baclofen were superior to clonidine and R-PIA.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/farmacología , Agonistas alfa-Adrenérgicos/farmacología , Analgésicos Opioides/farmacología , Baclofeno/farmacología , Clonidina/farmacología , Agonistas del GABA/farmacología , Morfina/farmacología , Neuralgia/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Animales , Conducta Animal/efectos de los fármacos , Femenino , Inyecciones Espinales , Isquemia/complicaciones , Isquemia/tratamiento farmacológico , Neuralgia/etiología , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio/farmacología , Médula Espinal/irrigación sanguínea , Médula Espinal/fisiopatologíaRESUMEN
The neuropeptide galanin may have a role in modulation of nociceptive input at spinal level. Here we report that mice over-expressing galanin exhibit significant elevation of nociceptive threshold to thermal stimulation in comparison to wild-type mice as assessed by the tail flick and paw heat irradiation tests. No change in response to mechanical or cold stimulation was seen. The elevated heat nociceptive threshold in the galanin over-expressing mice was reversed by intrathecal application of the putative galanin receptor antagonist M-35, galanin-(1-12)-pro-bradykinin-(2-9). The results thus support that galanin has an inhibitory function in rodent spinal cord.
Asunto(s)
Galanina/genética , Dimensión del Dolor , Umbral del Dolor/fisiología , Médula Espinal/fisiología , Animales , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Frío , Femenino , Galanina/farmacología , Expresión Génica/fisiología , Miembro Posterior , Calor , Masculino , Ratones , Ratones Transgénicos , Umbral del Dolor/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Estimulación Física , Médula Espinal/química , Cola (estructura animal)RESUMEN
Neuropeptide Y (NPY) is believed to exert antinociceptive actions by inhibiting the release of substance P and other 'pain neurotransmitters' in the spinal cord dorsal horn. However, the physiological significance and potential therapeutic value of NPY remain obscure. It is also unclear which receptor subtype(s) are involved. To identify a possible physiological role for the NPY Y1 receptor in pain transmission, we generated NPY Y1 receptor null mutant (Y1-/-) mice by homologous recombination techniques. Here we show that Y1-/- mice develop hyperalgesia to acute thermal, cutaneous and visceral chemical pain, and exhibit mechanical hypersensitivity. Neuropathic pain is increased, and the mice show a complete absence of the pharmacological analgesic effects of NPY. In the periphery, Y1 receptor activation is sufficient and required for substance P release and the subsequent development of neurogenic inflammation and plasma leakage. We conclude that the Y1 receptor is required for central physiological and pharmacological NPY-induced analgesia and that its activation is both sufficient and required for the release of substance P and initiation of neurogenic inflammation.
Asunto(s)
Dolor , Receptores de Neuropéptido Y/fisiología , Animales , Capsaicina , Marcación de Gen , Inflamación/etiología , Masculino , Ratones , Ratones Endogámicos BALB C , Mutagénesis , Dolor/inducido químicamente , Umbral del Dolor , Plasma , Receptores de Neuropéptido Y/genética , Sustancia P/metabolismoRESUMEN
The development of neuropathic-like behaviors following unilateral ischemic injury to the sciatic nerve was examined and compared in four rat strains: Sprague--Dawley (SD), Wistar--Kyoto (WK), spontaneously hypertensive (SHR) and Dark--Agouti (DA). We have also compared two sub-strains of SD rats supplied from two different vendors (SD-BK and SD-DK). The responses to mechanical, heat or cold stimuli of both hind paws were measured before and regularly after injury for up to 10 weeks. Spontaneous paw lifting and changes in paw posture after nerve injury were also examined. Significant differences in basal sensitivity to mechanical or heat stimulation were seen among the four rat strain studied with SHR and DA rats being less sensitive than the SD and WK rats. All strains of rats developed bilateral mechanical allodynia and ipsilateral heat hyperalgesia after photochemically-induced nerve ischemia, but the time-course and magnitude of the responses were significantly different among the strains. Again, the SHR and DA were found to be least susceptible to the development of abnormal pain-like responses. Cold allodynia occurred only in WK and SD-BK. SD-DK rats on the other hand developed more severe mechanical allodynia than SD-BK. SHR and DA rats showed less deficits in paw posture after nerve injury whereas spontaneous pain lifting, a measure of possible spontaneous pain, was comparable among all strains. Light microscopic study of the injured sciatic nerve showed comparable nerve damage in SHR, WK and two sub-strains of SD rats. The DA rats however exhibited reduced area of intraneural damage. Finally, electronmicroscopic examination revealed that damage to both myelinated and unmyelinated fibers occurred in this model in all strains. These results showed that normal sensitivity and the development of pain-like response after partial nerve injury differ substantially among different strains of rats, supporting the emerging concept that genetic factors affect pain sensitivity under normal conditions and after nerve injury. The apparent resistance of DA rats to nerve ischemia, however, may suggest that genetic factors not directly related to pain modulation also play a role in the diverse outcomes. Our results indicate that sub-strains of rats also showed variable development of neuropathic pain-like behaviors to both the modality and magnitude of the effect. Thus, controlling sub-strains is also important in experimental studies of neuropathic pain in rats.
Asunto(s)
Conducta Animal/fisiología , Isquemia/complicaciones , Isquemia/genética , Isquemia/patología , Dolor/etiología , Dolor/genética , Neuropatía Ciática/complicaciones , Neuropatía Ciática/genética , Animales , Frío , Calor , Dolor/patología , Dimensión del Dolor , Estimulación Física , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Tiempo de Reacción , Flujo Sanguíneo Regional/fisiología , Neuropatía Ciática/patología , Especificidad de la Especie , Factores de TiempoRESUMEN
BACKGROUND: There is often no satisfactory treatment for chronic pain after spinal cord injury. We have previously reported that intrathecal (i.t.) administration of the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) or the opioid morphine has anti-allodynic effects in a model of presumed chronic central pain after photochemically induced spinal cord injury in rats. In the present study, we set out to investigate the possible interaction between i.t. R-PIA and morphine in spinally injured rats. METHODS: Sprague-Dawley rats displaying allodynia-like behaviors to mechanical and cold stimuli after photochemically induced spinal cord injury with minor motor deficits were used. R-PIA and morphine, either alone or in combination, were administered i.t. through an implanted catheter to lumbar spinal cord. RESULTS: Cumulative doses of R-PIA or morphine dose-dependently reduced the mechanical allodynia-like behavior, with a threshold of 1 nmol and 1.5 nmol, respectively. When co-administrated, R-PIA and morphine produced marked suppression of mechanical allodynia at doses of 5 pmol and 7.5 pmol, respectively. The effect of i.t. co-administration of R-PIA and morphine on cold allodynia was comparable to i.t. R-PIA alone. The combination of R-PIA and morphine did not increase adverse effects such as motor deficits in comparison to either drug alone. CONCLUSION: These results demonstrate a supra-additive interaction between the adenosine A1-receptor agonist R-PIA and morphine to reduce mechanical allodynia-like behavior in rats with chronic spinal cord injury. The combination of R-PIA and morphine administered spinally may be superior to R-PIA or morphine alone for treating such pain.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Morfina/uso terapéutico , Dolor/tratamiento farmacológico , Fenilisopropiladenosina/uso terapéutico , Agonistas del Receptor Purinérgico P1 , Analgésicos Opioides/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Inyecciones Espinales , Morfina/administración & dosificación , Dolor/psicología , Fenilisopropiladenosina/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
A mouse model of neuropathic pain was developed by a photochemically induced ischemic nerve injury in normal male C57/BL6 mice. The ischemia was induced by unilateral irradiation of the sciatic nerve with an argon ion laser after intravenous administration of a photosensitizing dye, erythrosin B. The nerve injury resulted in a significant decrease in withdrawal threshold of the hindpaws to mechanical stimulation with von Frey hairs, as well as increased responsiveness to cold and heat stimulation. The mice, however, did not exhibit overt spontaneous pain-like behaviors. The evoked pain-related behaviors were observed bilaterally, although the ipsilateral changes were greater than on the contralateral side. The extent and time course of the behavioral changes were related to the duration of laser irradiation, with 1-min exposure producing the most consistent effect. Morphological examination at the light microscopic level revealed partial demyelination and axonal degeneration of the large myelinated fibers at the epicenter of the lesion 1 week postirradiation. The extent of the damage was correlated with the duration of irradiation. Injury and loss of unmyelinated fibers were also observed at the electronmicroscopic level. We conclude that an intravascular photochemical reaction leading to ischemia results in graded damage to the sciatic nerve in mice. Moreover, the nerve injury is associated with the development of abnormal pain-related behaviors. Both the behavioral and the morphological changes are correlated with the duration of irradiation. These results establish a mouse model of partial nerve injury with neuropathic pain-like behaviors which may be useful in studies using genetically modified mice.
Asunto(s)
Modelos Animales de Enfermedad , Neuralgia/fisiopatología , Nervio Ciático/irrigación sanguínea , Nervio Ciático/lesiones , Neuropatía Ciática/fisiopatología , Animales , Conducta Animal , Frío , Eritrosina , Colorantes Fluorescentes , Calor , Isquemia/etiología , Rayos Láser , Masculino , Ratones , Ratones Endogámicos C57BL , Estimulación Física , Traumatismos Experimentales por Radiación/complicaciones , Tiempo de Reacción , Nervio Ciático/patología , Neuropatía Ciática/etiología , Neuropatía Ciática/patologíaRESUMEN
The effect of systemic gabapentin, a novel antiepileptic and analgesic, was tested on allodynia-like behaviors in spinal cord injured rats. On the first day of treatment 30 mg/kg intraperitoneal gabapentin did not alleviate hyper-reactivity to mechanical and cold stimulation. The allodynia was significantly reduced by 100 mg/kg gabapentin, which however, produced sedation and motor impairments. Repeated administration of 30 mg/kg gabapentin once a day produced a gradually increasing anti-allodynic effect. Total alleviation of mechanical allodynia was observed in most rats after the third administration of gabapentin. Thus, build-up of the antiallodynic effect of gabapentin may develop through a time dependent mechanism or alternatively through a gradual accumulation of the effective central nervous system concentration of the drug.
Asunto(s)
Acetatos/farmacología , Aminas , Analgésicos/farmacología , Ácidos Ciclohexanocarboxílicos , Dolor/prevención & control , Traumatismos de la Médula Espinal/fisiopatología , Ácido gamma-Aminobutírico , Acetatos/administración & dosificación , Analgésicos/administración & dosificación , Animales , Frío , Esquema de Medicación , Femenino , Gabapentina , Inyecciones Intraperitoneales , Dolor/etiología , Dolor/fisiopatología , Estimulación Física , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Increased response to mechanical or cold stimulation of hind paws was observed in rats with partial sciatic nerve injury as a result of photochemically induced ischemia. The present study examined the effects of intrathecal morphine, clonidine and baclofen on the allodynia-like responses. METHODS: The left sciatic nerves of rats were irradiated for 2 min with an argon ion laser under chloral hydrate anesthesia. The threshold of paw withdrawal to mechanical stimulation was determined with a series of monofilaments (von Frey hairs). The response to cold stimulation was tested by spraying ethyl chloride on the plantar surface of the paw. When rats were exhibiting stable mechanical and cold allodynia-like behaviors after nerve injury, the effects of i.t. morphine (1, 2, 7 microg), clonidine (1, 2, 7 microg) and baclofen (0.1, 0.2, 0.7, 9 microg) in a cumulative dose regime were investigated. RESULTS: Intrathecal morphine dose-dependently alleviated the mechanical and cold allodynia without inducing motor impairment or sedation. Intrathecal clonidine did not alter the response of hind paws to mechanical stimulation, but reduced the cold allodynia. Intrathecal baclofen reduced the responses of rats to mechanical stimulation only at doses that also induced profound motor deficits. CONCLUSIONS: The present data suggest that intrathecal morphine, and to some extent clonidine, but not baclofen, alleviated the abnormal pain-related behaviors in this new rat model of partial peripheral nerve injury. Differences in the pharmacological profile between the present model and other models of peripheral nerve injury are discussed.
Asunto(s)
Analgésicos/administración & dosificación , Baclofeno/administración & dosificación , Clonidina/administración & dosificación , Agonistas del GABA/administración & dosificación , Morfina/administración & dosificación , Dolor/tratamiento farmacológico , Nervio Ciático/lesiones , Analgésicos Opioides/administración & dosificación , Animales , Frío , Relación Dosis-Respuesta a Droga , Inyecciones Espinales , Masculino , Dolor/etiología , Estimulación Física , Ratas , Ratas Sprague-DawleyRESUMEN
The intrathecal (i.t.) administration of the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) reduced pain-related behaviors after peripheral nerve or spinal cord injury in rats. The endogenous ligand adenosine is clinically available and has been tested i.t. as an analgesic. Thus, we set out to investigate whether i.t. adenosine could reduce allodynia in a model of central pain in spinally injured rats. I.t. adenosine did not reduce mechanical and cold allodynia-like behaviors at doses of 10, 100 and 187 nmol, whereas i.t. R-PIA at 10 nmol markedly alleviated allodynia in the same animals. The lack of effect by exogenous adenosine may be due to pharmacokinetic or pharmacodynamic reasons. Alternatively, adenosine may have reduced affinity and selectivity towards the A1-receptors which may be important for the antiallodynic effect.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Femenino , Inyecciones Espinales , Actividad Motora/efectos de los fármacos , Dimensión del Dolor , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Traumatismos de la Médula Espinal/inducido químicamenteRESUMEN
We have examined the effects of intrathecal (i.t.) administration of [Leu31,Pro34]-neuropeptide Y (NPY) or NPY-(13-36), selective agonists of NPY Y1 or Y2 receptors, respectively, on the excitability of the flexor reflex in normal rats and after unilateral transection of the sciatic nerve. In rats with intact and sectioned sciatic nerves, i.t. [Leu31,Pro34]-NPY induced a similar biphasic effect on the flexor reflex with facilitation at low doses and facilitation followed by depression at high doses. In contrast, i.t. NPY-(13-36) only facilitated the flexor reflex in normal rats, and at high dose it caused ongoing discharges in the electromyogram. NPY-(13-36) caused dose-dependent depression of the flexor reflex in rats after sciatic nerve transection, in addition to its facilitatory effect. Topical application of [Leu31,Pro34]-NPY or NPY-(13-36) caused a moderate and brief reduction in spinal cord blood flow. No difference was noted between the vasoconstrictive effect of [Leu31,Pro34]-NPY and NPY-(13-36). It is suggested that activation of Y1 receptors may be primarily responsible for the reflex depressive effect of i.t. neuropeptide Y in rats with intact sciatic nerves, whereas both Y1 and Y2 receptors may be involved in mediating the depressive effect of NPY after axotomy.
Asunto(s)
Neuropéptido Y/farmacología , Fragmentos de Péptidos/farmacología , Receptores de Neuropéptido Y/agonistas , Reflejo/efectos de los fármacos , Animales , Axotomía , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Espinales , Neuropéptido Y/análogos & derivados , Nociceptores/fisiología , Dolor/fisiopatología , Nervio Peroneo/cirugía , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/fisiología , Médula Espinal/irrigación sanguínea , Médula Espinal/química , Médula Espinal/fisiología , Nervio Tibial/cirugíaRESUMEN
The present study examined the effects of spinal cord ischemia on the expression of mu-opioid receptors in rat dorsal spinal cord and the effects of intrathecal (i.t.) morphine on the acute mechanical allodynia that developed after spinal ischemia. The mechanical allodynia was not significantly alleviated by up to 10 microg i.t. morphine, a dose which caused strong antinociception in the tail flick test. Immunohistochemical staining demonstrated that the level of mu-opioid receptor expression in the dorsal horn of spinal cord segments receiving input from the allodynic skin was markedly reduced 2 days after ischemia, when the rats were allodynic. The results indicate that spinal cord ischemia reduces the expression of mu-opioid receptors in rat dorsal horn, which may be one of the underlying mechanisms of morphine insensitivity for treating acute allodynia after spinal ischemia.
Asunto(s)
Analgésicos Opioides/farmacología , Isquemia/metabolismo , Morfina/farmacología , Receptores Opioides mu/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Animales , Péptido Relacionado con Gen de Calcitonina/análisis , Encefalina Metionina/análisis , Femenino , Hiperalgesia/metabolismo , Inmunohistoquímica , Modelos Lineales , Ratas , Ratas Sprague-Dawley , Receptores Opioides mu/fisiología , Médula Espinal/irrigación sanguínea , Estrés Mecánico , Sustancia P/análisisRESUMEN
We have previously suggested that the neuropeptides galanin and galanin message-associated peptide (GMAP) may have an inhibitory role in spinal nociception. The present study examined the effects of intrathecal (i.t.) administration of these two peptides on allodynia-like behaviours in response to mechanical and cold stimulation in rats after photochemically induced ischaemic peripheral nerve injury. I.t. galanin significantly alleviated the mechanical- and cold-allodynia-like behaviours in nerve injured rats, and was not associated with motor impairment or sedation. I.t. GMAP relieved mechanical allodynia much less than galanin. I.t. M-35, a high-affinity galanin receptor antagonist, did not significantly alter the response of the rats to mechanical or cold stimulation. At 1 or 2 weeks postinjury, around 15% of dorsal root ganglion (DRG) neuron profiles showed galanin-like immunoreactivity. These profiles were mostly small sized. Although the number of galanin positive cells was thus increased in the DRG in the present model, the increase was substantially less than after complete sciatic nerve section, as previously shown. The present results showed that spinal administration of galanin inhibited some abnormal pain-like behaviours in rats after partial peripheral nerve injury. These results further support an inhibitory function for galanin in nociception. However, endogenous galanin may not play a significant role in suppressing nociceptive input after partial ischaemic peripheral nerve injury, as the upregulation of galanin is moderate.
Asunto(s)
Galanina/farmacología , Hiperalgesia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Nervio Ciático/lesiones , Animales , Conducta Animal/efectos de los fármacos , Frío , Galanina/análisis , Ganglios Espinales/química , Hiperalgesia/etiología , Inmunohistoquímica , Inyecciones Espinales , Isquemia/complicaciones , Isquemia/tratamiento farmacológico , Masculino , Nociceptores/efectos de los fármacos , Dolor/etiología , Traumatismos Experimentales por Radiación/complicaciones , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Nervio Ciático/irrigación sanguínea , Nervio Ciático/efectos de la radiación , Estrés MecánicoRESUMEN
UNLABELLED: We examined the development of tolerance to the antiallodynic effect of chronic intrathecal (IT) administration of the adenosine analog R-phenylisopropyladenosine (R-PIA) in a rat model of central pain after ischemic spinal cord injury. After 10 days of IT R-PIA treatment, the effect of IT morphine was also assessed to examine whether cross-tolerance between R-PIA and morphine was present. IT R-PIA completely alleviated allodynia-like behaviors to mechanical and cold stimuli in spinally injured rats. The anti-allodynic effect of R-PIA was maintained for 6-7 days with twice-daily administration and was reduced thereafter, particularly with respect to cold allodynia. IT morphine alleviated mechanical and cold allodynia in rats rendered tolerant to R-PIA to a degree comparable to that in R-PIA-naive (control) rats, which indicates that the anti-allodynic property of R-PIA is independent of the mechanisms by which morphine acts. The possibility of using agonists of adenosine receptors in treating refractory pain in patients with spinal cord injury is discussed. IMPLICATIONS: There is often no satisfactory treatment for chronic pain after spinal cord injury. Our study suggests such pain can be treated with a spinal injection of R-phenylisopropyladenosine in rats. Reduced effect to R-phenylisopropyladenosine was noted with repeated administrations. However, there was no cross-tolerance to morphine.
Asunto(s)
Adenosina/análogos & derivados , Analgésicos Opioides/administración & dosificación , Analgésicos/administración & dosificación , Morfina/administración & dosificación , Dolor/tratamiento farmacológico , Agonistas del Receptor Purinérgico P1 , Traumatismos de la Médula Espinal/complicaciones , Adenosina/administración & dosificación , Animales , Enfermedad Crónica , Tolerancia a Medicamentos , Femenino , Inyecciones Espinales , Dolor/etiología , Ratas , Ratas Sprague-DawleyRESUMEN
Peptide nucleic acids (PNAs) form stable and tight complexes with complementary DNA and/or RNA and would be promising antisense reagents if their cellular delivery could be improved. We show that a 21-mer PNA, complementary to the human galanin receptor type 1 mRNA, coupled to the cellular transporter peptides, transportan or pAntennapedia(43-58), is efficiently taken up into Bowes cells where they block the expression of galanin receptors. In rat, the intrathecal administration of the peptide-PNA construct results in a decrease in galanin binding in the dorsal horn. The decrease in binding results in the inability of galanin to inhibit the C fibers stimulation-induced facilitation of the rat flexor reflex, demonstrating that peptide-PNA constructs act in vivo to suppress expression of functional galanin receptors.
Asunto(s)
Proteínas Nucleares , Dolor/fisiopatología , Ácidos Nucleicos de Péptidos/metabolismo , Receptores de Neuropéptido/metabolismo , Transducción de Señal , Factores de Transcripción , Secuencia de Aminoácidos , Animales , Proteína con Homeodominio Antennapedia , Secuencia de Bases , Regulación hacia Abajo , Femenino , Galanina , Proteínas de Homeodominio/química , Proteínas de Homeodominio/metabolismo , Humanos , Melanoma/metabolismo , Melanoma/patología , Melanoma/fisiopatología , Datos de Secuencia Molecular , Dolor/metabolismo , Fragmentos de Péptidos/metabolismo , Ácidos Nucleicos de Péptidos/química , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptor de Galanina Tipo 1 , Receptores de Galanina , Receptores de Neuropéptido/genética , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Médula Espinal/metabolismo , Células Tumorales Cultivadas , Venenos de AvispasRESUMEN
We examined the effects of intrathecal (i.t.) selective opioid receptor agonists in alleviating mechanical and cold allodynia in spinally injured rats. Both DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, a mu-opioid receptor agonist) and DPDPE ([D-Phe2,D-Phe5]-enkephalin, a delta-opioid receptor agonist) dose-dependently relieved the chronic allodynia-like behavior at doses selective for their respective receptors. The anti-allodynic effect of DAMGO and DPDPE was reversed by the selective mu- and delta-opioid receptor antagonists CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) and naltrindole, respectively. In contrast, the selective kappa-opioid receptor agonist U50488H did not alleviate the allodynia-like behavior, but rather enhanced it. The anti-nociceptive and anti-allodynic effect of i.t. DAMGO was blocked by U50488H. Thus, activation of spinal mu- and delta-, but not kappa-opioid receptors produced anti-allodynic effect in this model of central pain. Drugs which act selectively on opioid receptor subtypes may be useful in managing chronic central pain of spinal cord origin.