Medullary control of nociceptive transmission: reciprocal dual communication with the spinal cord

Control of pain perception, essential for organism surviving and recovery from disease, is exerted by higher brain centers integrating nociception with emotional and cognitive information and modulating the brainstem-spinal feedback loops that regulate spinal nociceptive transmission. Development of chronic pain deregulates the forebrain-brainstem-spinal pain control system, which leads to neuroplasticity and disruption of a balanced brain-spinal communication. Targets for impeding pain chronification are being developed using the manipulation of the cross talk between brain and dorsal horn, at both sites of the loop.FCT -Fuel Cell Technologies Program(POCTI/NSE/46399/2002

Brain afferents to the medullary dorsal reticular nucleus: a retrograde and anterograde tracing study in the rat

The medullary dorsal reticular nucleus (DRt) was recently shown to belong to the supraspinal pain control system; neurons within this nucleus give origin to a descending projection that increases spinal nociceptive transmission and facilitates pain perception [Almeida et al. (1999), Eur. J. Neurosci., 11, 110-122]. In the present study, the areas of the brain that may modulate the activity of DRt neurons were investigated by using of tract-tracing techniques. Injection of a retrograde tracer into the DRt resulted in labelling in multiple areas of the brain. In the contralateral orbital, prelimbic, infralimbic, insular, motor and somatosensory cortices labelling was prominent, but a smaller ipsilateral projection from these same areas was also detected. Strong labelling was also noted in the central amygdaloid nucleus, bed nucleus of stria terminalis and substantia innominata. Labelled diencephalic areas were mainly confined to the hypothalamus, namely its lateral and posterior areas as well as the paraventricular nucleus. In the mesencephalon, the periaqueductal grey, red nucleus and deep mesencephalic nucleus were strongly labelled, whereas, in the brainstem, the parabrachial nuclei, rostroventromedial medulla, nucleus tractus solitarius, spinal trigeminal nucleus, and the parvocellular, dorsal, lateral and ventral reticular nuclei were the most densely labelled regions. All deep cerebellar nuclei were labelled bilaterally. These data suggest that the DRt integrates information from the somatosensory, antinociceptive, autonomic, limbic, pyramidal and extrapyramidal systems while triggering its descending facilitating action upon the spinal nociceptive transmission.BIOTECH project n° BIO4-CT98-007676.Pain Gulbenkian Programme.Fundação para a Ciência e a Tecnologia (FCT) - project POCTI/NSE/38952/2001

Microglial responses to amyloid β peptide opsonization and indomethacin treatment

BACKGROUND: Recent studies have suggested that passive or active immunization with anti-amyloid β peptide (Aβ) antibodies may enhance microglial clearance of Aβ deposits from the brain. However, in a human clinical trial, several patients developed secondary inflammatory responses in brain that were sufficient to halt the study. METHODS: We have used an in vitro culture system to model the responses of microglia, derived from rapid autopsies of Alzheimer's disease patients, to Aβ deposits. RESULTS: Opsonization of the deposits with anti-Aβ IgG 6E10 enhanced microglial chemotaxis to and phagocytosis of Aβ, as well as exacerbated microglial secretion of the pro-inflammatory cytokines TNF-α and IL-6. Indomethacin, a common nonsteroidal anti-inflammatory drug (NSAID), had no effect on microglial chemotaxis or phagocytosis, but did significantly inhibit the enhanced production of IL-6 after Aβ opsonization. CONCLUSION: These results are consistent with well known, differential NSAID actions on immune cell functions, and suggest that concurrent NSAID administration might serve as a useful adjunct to Aβ immunization, permitting unfettered clearance of Aβ while dampening secondary, inflammation-related adverse events

Supraspinal opioid delta receptor mediated antinociception: Supraspinal modulation of neuropathic pain

The central objective of this dissertation focuses on the influence of supraspinal descending nociceptive inhibitory and facilitatory systems in the modulation of both nociceptive input and neuropathic pain states due to peripheral nerve injury. Opioid delta-mediated antinociception within the RVM was observed to modulate supraspinally organized nociceptive behavior to acute stimuli. Spinally organized nociceptive behavior was observed to be δ-mediated as well, but appeared to be stimulus intensity dependent. In addition, activation of δ-opioid receptors within the RVM elicited a dose-dependent antinociceptive effect to tonic forms of nociceptive input. Lesioning of the dorsal lateral funiculus (DLF) was observed to block both the antinociceptive effect of δ-opioid receptor activation in the RVM and attenuation of FLI in the lumbar spinal cord. Finally, concurrent administration of delta-opioid receptor selective agonists into the RVM and intrathecally elicited a synergistic antinociceptive effect to acute forms of nociceptive stimuli. Taken together, these studies presented in this dissertation suggest that activation of δ-opioid receptors within the RVM elicits an antinociceptive effect to both acute and tonic forms of nociceptive input by way of a descending nociceptive inhibitory pathway localized within the DLF. Increased levels, or activity, of supraspinal CCK may consequent to tonic activation of an on-cell descending nociceptive facilitatory system and the behavioral signs of neuropathic pain. For example, CCK levels in the caudal brainstem, when quantified by protein immunoassay, were higher in those animals that had received a ligation to the L5/L6 spinal nerves in comparison to sham operated animals. Administration of the CCK(B) receptor antagonist L365,260 into the RVM was observed to reverse both tactile allodynia and thermal hyperalgesia in L5/L6 ligated animals. In addition, administration of CCK-8 sulfate into the RVM was observed to produce tactile allodynia as well as thermal hyperalgesia, but to a lesser extent, in otherwise normal animals. Finally, a loss of morphine efficacy, when administered into the PAG, was restored by the administration of L365,260 into the RVM of L₅/L₆ ligated animals. Taken together, these studies presented in this dissertation suggest the involvement of a supraspinal descending nociceptive facilitatory influence in the modulation of neuropathic pain due to peripheral nerve injury