RESUMO
Pontospinal noradrenergic neurons form a component of an endogenous analgesic system and represent a potential therapeutic target. We tested the principle that genetic manipulation of their excitability can alter nociception using an adenoviral vector (AVV-PRS-hKir(2.1)) containing a catecholaminergic-selective promoter (PRS) to retrogradely transduce and inhibit the noradrenergic neurons projecting to the lumbar dorsal horn through the expression of a potassium channel (hKir(2.1)). Expression of hKir(2.1) in catecholaminergic PC12 cells hyperpolarized the membrane potential and produced a barium-sensitive inward rectification. LC neurons transduced by AVV-PRS-hKir(2.1) in slice cultures also showed barium-sensitive inward rectification and reduced spontaneous firing rate (median 0.2 Hz; n = 19 vs control 1.0 Hz; n = 18, p < 0.05). Pontospinal noradrenergic neurons were retrogradely transduced in vivo by injection of AVV into the lumbar dorsal horn (L4-5). Rats transduced with AVV-PRS-hKir(2.1) showed thermal but not mechanical hyperalgesia. Similar selective augmentation of thermal hyperalgesia was seen in the CFA-inflammatory pain model after AVV-PRS-hKir(2.1). In the formalin test, rats transduced with hKir(2.1) showed enhanced nocifensive behaviors (both Phase I and II, p < 0.05, n = 11/group) and increased c-Fos-positive cells in the lumbar dorsal horn. Transduction with AVV-PRS-hKir(2.1) before spared nerve injury produced no change in tactile or cold allodynia. Thus, the selective genetic inhibition of approximately 150 pontospinal noradrenergic neurons produces a modality-specific thermal hyperalgesia, increased nocifensive behaviors, and spinal c-Fos expression in the formalin test, but not in the spared nerve injury model of neuropathic pain, indicating that these neurons exert a selective tonic restraining influence on in vivo nociception.
Assuntos
Vetores Genéticos/genética , Hiperalgesia/etiologia , Hiperalgesia/patologia , Neurônios/metabolismo , Norepinefrina/metabolismo , Ponte/patologia , Adenoviridae/genética , Animais , Animais Recém-Nascidos , Catecolaminas/genética , Contagem de Células/métodos , Modelos Animais de Doenças , Dopamina beta-Hidroxilase/metabolismo , Proteínas de Fluorescência Verde/genética , Técnicas In Vitro , Laminectomia/métodos , Masculino , Potenciais da Membrana/genética , Potenciais da Membrana/fisiologia , Atividade Motora/genética , Células PC12 , Medição da Dor/métodos , Limiar da Dor/fisiologia , Técnicas de Patch-Clamp/métodos , Doenças do Sistema Nervoso Periférico/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/genética , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Transfecção/métodosRESUMO
The aetiology of central post-stroke pain (CPSP) is poorly understood and such pains are often refractory to treatment. We report the case of a 56-year-old man, who, following a temporo-parietal infarct, suffered from debilitating and refractory hemi-body cold dysaesthesia and severe tactile allodynia. This was associated with thermal and tactile hypoaesthesia and hypoalgesia on his affected side. Implantation of a deep brain stimulating electrode in his periventricular gray (PVG) region produced an improvement in his pain that was associated with a striking normalisation of his deficits in somatosensory perception. This improvement in pain and thermal sensibility was reversed as stimulation became less effective, because of increased electrode impedance. Therefore, we postulate that the analgesic benefit may have occurred as a consequence of the normalisation of somatosensory function and we discuss these findings in relation to the theories of central pain generation and the potential to engage useful plasticity in central circuits.
