Systemic morphine suppresses noxious stimulus-evoked Fos protein-like immunoreactivity in the rat spinal cord

Abstract

Previous experiments have shown that noxious stimulation increases expression of the c-fos proto-oncogene in subpopulations of spinal cord neurons. c-fos expression was assessed by immunostaining for Fos, the nuclear phosphoprotein product of the c-fos gene. In this study, we examined the effect of systemic morphine on Fos-like immunoreactivity (FLI) evoked in the formalin test, a widely used model of persistent pain. Awake rats received a subcutaneous 150 microliters injection of 5% formalin into the plantar aspect of the right hindpaw. The pattern of nuclear FLI was consistent with the known nociceptive primary afferent input from the hindpaw. Dense labeling was recorded in the superficial dorsal horn (laminae I and IIo) and in the neck of the dorsal horn (laminae V and VI), areas that contain large populations of nociceptive neurons. Sparse labeling was noted in lamina IIi and in the nucleus proprius (laminae III and IV), generally considered to be nonnociceptive areas of the cord. Fos immunoreactivity was also evoked in the ventromedial gray, including laminae VII, VIII, and X. There was no labeling in lamina IX of the ventral horn. Since FLI was time dependent and distributed over several spinal segments, we focused our analysis where maximal staining was found (L3-L5) and at the earliest time point of the peak Fos immunoreactivity (2 hr). Twenty minutes prior to the formalin injection, the rats received morphine (1.0, 2.5, 5.0, or 10 mg/kg, s.c.) or saline vehicle. Two hours later, the rats were killed, their spinal cords removed, and 50 microns transverse sections of the lumbar enlargement were immunostained with a rabbit polyclonal antiserum directed against Fos. Prior treatment with morphine sulfate profoundly suppressed formalin-evoked FLI in a dose-dependent and naloxone-reversible manner. The dose-response relationship of morphine-induced suppression of FLI varied in different laminae. To quantify the effect of morphine on FLI, labeled neurons in sections taken from the L4/5 level of each rat were plotted with a camera lucida and counted. Staining in the neck of the dorsal horn (laminae V and VI) and in more ventral laminae VII, VIII, and X, was profoundly suppressed by doses of morphine which also suppress formalin-evoked behavior. Although the labeling was also significantly reduced in laminae I and II, at the highest doses of morphine there was substantial residual labeling in the superficial dorsal horn. These data indicate that analgesia from systemic opiates involves differential regulation of nociceptive processing in subpopulations of spinal nociceptive neurons.

Transient functional connections between the developing corticospinal tract and cervical spinal interneurons as demonstrated by c-fos immunohistochemistry

“…The resem blance with the c-fos expression in walking rats is striking [9]. Secondly, the population of Fos-Li neurons in the medial parts of the dorsal horn closely resembles that encountered after noxious stimulation [1,20,23].…”

L’analgésie préventive expérimentale, quelle est sa valeur clinique?

“…Indeed, analgesic drugs, such as opioids, given before the injury reduce the extent of c-fos expression in a dose-dependent manner. 15 Histochemical studies in the rat central nervous system suggest that expression of the c-fos proto-oncogene, as measured by Fos protein immunocytochemistry, is a useful marker of neuronal activity that can be used to map functionally related neural pathways. 15 Broadly speaking, there are two main types of tests of nociception and analgesia.…”

“…15 Histochemical studies in the rat central nervous system suggest that expression of the c-fos proto-oncogene, as measured by Fos protein immunocytochemistry, is a useful marker of neuronal activity that can be used to map functionally related neural pathways. 15 Broadly speaking, there are two main types of tests of nociception and analgesia. In the first type of tests, the response to the stimulation is fixed and the test measures mainly the threshold of the stimulus required to elicit this response.…”

“…Les analgésiques, comme les opioïdes, donnés avant la lésion réduisent l'expression de c-fos en proportion de la dose. 15 Les études histochimiques du SNC du rat suggèrent que l'expression du proto-oncogène c-fos, mesurée par immunocytochimie de la protéine Fos, soit un marqueur utile de l'activité neuronale utilisable pour cartographier les voies nerveuses dont les fonctions sont reliées. 15 De façon générale, il existe deux catégories principales de test de nociception et d'analgésie.…”

“…15 Les études histochimiques du SNC du rat suggèrent que l'expression du proto-oncogène c-fos, mesurée par immunocytochimie de la protéine Fos, soit un marqueur utile de l'activité neuronale utilisable pour cartographier les voies nerveuses dont les fonctions sont reliées. 15 De façon générale, il existe deux catégories principales de test de nociception et d'analgésie. Dans la première, la réponse à la stimulation est fixe et on mesure essentiellement le stimulus seuil requis pour déclencher cette réponse, comme pour les techniques de stimulation calorique de la queue et de la plaque chauffante.…”