RESUMEN
UNLABELLED: This study investigated the analgesic potency and site of action of systemic dexmedetomidine, a selective alpha2-adrenoceptor (alpha2AR) agonist, in normal and neuropathic rats. Ligation of the L5-6 spinal nerves produced a chronic mechanical and thermal neuropathic hyperalgesia in rats. von Frey fibers and a thermoelectric Peltier device were used to measure mechanical and heat withdrawal thresholds over the hindpaw. Systemic dexmedetomidine dose-dependently increased the mechanical and thermal thresholds in the control animals (50% effective dose [ED50] 144 and 180 microg/kg intraperitoneally [i.p.], respectively). Neuropathic animals responded to much smaller doses of dexmedetomidine with mechanical and thermal ED50 values of 52 and 29 microg/kg i.p., respectively. There was no difference between the control and neuropathic animals with respect to dexmedetomidine-evoked sedation, as determined by decreased grid crossings in an open-field activity chamber (ED50 12 and 9 microg/kg i.p., respectively). Atipamezole, a selective alpha2AR antagonist, blocked the analgesic and sedative actions of dexmedetomidine inboth the neuropathic and control animals. However, L-659,066, a peripherally restricted alpha2AR antagonist, could only block the analgesic actions of dexmedetomidine in the neuropathic rats, with no effect in control animals. In conclusion, nerve injury enhanced the analgesic but not the sedative potency of systemic dexmedetomidine and may have shifted the site of alpha2 analgesic action to outside the blood-brain barrier. IMPLICATIONS: We tested the analgesic efficacy of the alpha2 agonist dexmedetomidine in normal and nerve-injured rats. The analgesic potency of dexmedetomidine was enhanced after nerve injury with a site of action outside the central nervous system. Peripherally restricted alpha2 agonists may be useful in the management of neuropathic pain.
Asunto(s)
Agonistas alfa-Adrenérgicos/uso terapéutico , Analgésicos no Narcóticos/uso terapéutico , Imidazoles/uso terapéutico , Nervios Espinales/lesiones , Antagonistas Adrenérgicos alfa/farmacología , Analgésicos no Narcóticos/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Imidazoles/antagonistas & inhibidores , Imidazoles/farmacología , Masculino , Medetomidina , Dolor/tratamiento farmacológico , Dolor/etiología , Dolor/fisiopatología , Umbral del Dolor , Quinolizinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
We have reported that electrical or glutamate stimulation of the dorsolateral surface of the cervical spinal cord elicits a 40-60% decrease in renal sympathetic activity (RSA) in anesthetized rats. Because evoked sympatho-inhibition was observed, however, only after transection of the cervical spinal cord at C1, we suggested that unidentified supraspinal neurons affect the regulation of RSA by cervical neurons. In the present experiments, we tested the hypothesis that the modulatory supraspinal neurons are located in the ventrolateral medulla by observing the effects of rostroventral, lateral, medullary (RVLM) injections of the GABAergic agonist, muscimol, on baseline RSA and on our ability to inhibit that activity by cervical stimulation. GABAergic inhibition in the RVLM of chlorolose anesthetized rats elicited changes in RSA that were similar to those observed after transection of the spinal cord, including a 41% decrease in mean arterial pressure and a 44% increase in RSA. Moreover, after muscimol inhibition of RVLM neurons, electrical or glutamate stimulation of the dorsolateral cervical spinal cord elicited a decrease in RSA in otherwise intact rats. These results suggest that neurons in the RVLM interact with neurons in the cervical spinal cord in the regulation of RSA.
Asunto(s)
Glutamatos/farmacología , Riñón/inervación , Bulbo Raquídeo/fisiología , Cuello/inervación , Médula Espinal/fisiología , Sistema Nervioso Simpático/fisiología , Animales , Estimulación Eléctrica , Ácido Glutámico , Riñón/efectos de los fármacos , Masculino , Bulbo Raquídeo/efectos de los fármacos , Microinyecciones , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
We previously reported that electrical or glutamate stimulation of the cervical spinal cord elicits a 40-60% decrease in renal sympathetic nerve activity (RSA) in the anesthetized rats. This sympatho-inhibition was possible, however, only after transection of the spinal cord at C1 or GABAergic inhibition of neurons in the rostral ventrolateral medulla. We postulated that cervical neurons inhibit RSA by inhibiting the activity of spinal interneurons that are antecedent to sympathetic preganglionic neurons (SPNs), and that these interneurons may be, in turn, excited by afferent signals. In this study, we tested the hypothesis that cervical neurons can inhibit visceroceptive thoracic spinal neurons. We recorded the spontaneous and evoked activity of 45 dorsal horn neurons responsive to splanchnic stimulation before, during, and after chemical or electrical stimulation of the cervical spinal cord in chloralose-anesthetized spinal rats. Cervical spinal stimulation that inhibited RSA also inhibited the spontaneous and/or evoked activity of 44 dorsal horn neurons. In addition to inhibiting splanchnic-evoked neuronal responses, cervical stimulation also inhibited responses, in the same neurons, evoked by noxious heat or light brushing of receptive dermatomes. We concluded that cervical neurons participate in propriospinal inhibition of afferent transmission and that this inhibitory system may be involved in controlling the access of afferent information to SPNs.
Asunto(s)
Cuello/inervación , Neuronas/fisiología , Médula Espinal/fisiología , Sistema Nervioso Simpático/fisiología , Transmisión Sináptica/fisiología , Tórax/inervación , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Animales , Estimulación Eléctrica , Glutamatos/farmacología , Ácido Glutámico , Masculino , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Médula Espinal/citología , Médula Espinal/efectos de los fármacos , Nervios Esplácnicos/fisiología , Sistema Nervioso Simpático/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
In a previous study we reported that human/rat corticotropin-releasing factor (CRF) displayed antinociceptive activity in the mouse abdominal constriction assay. In this investigation we examined the effects of CRF on the evoked response of wide dynamic range (WDR) trigeminal neurons to noxious heat. Single units were recorded from the spinal trigeminal nucleus of urethane anesthetized rats. CRF inhibited the evoked response of these units in a dose-dependent manner with an ED50 of 2.3-7 nmol/kg i.v. Neither naloxone nor chlorisondamine pretreatment prevented the inhibitory actions of CRF. CRF-induced inhibition was also present in adrenalectomized and hypophysectomized animals. Intracerebroventricular administration of CRF did not inhibit the heat evoked response of WDR trigeminal units. alpha-Helical CRF, a CRF receptor antagonist, 12 nmol/kg i.v., alone did not affect the response of trigeminal units to heat, but pretreatment of animals with this dose blocked the inhibitory actions of CRF. By contrast to the inhibitory effects of CRF on heat-responsive units, CRF, 6-18 nmol/kg i.v., increased the spontaneous discharge rate of cold-responsive units by 57 +/- 16%. The data show that CRF selectively inhibits neuronal responses to noxious heat, an action that is independent of the pituitary-adrenal axis. These results are viewed as further evidence that CRF has antinociceptive properties in the periphery.