There is now abundant evidence that brain microglia, when activated, have the lineage, receptors, and synthetic capacity to participate in both potentially neurotoxic inflammatory responses and potentially beneficial phagocytic responses. Amyloid ␤ peptide (A␤) forms highly insoluble, ␤-pleated aggregates that are widely deposited in the Alzheimer's disease (AD) cortex and limbic system. Aggregated A␤ also activates the classical and alternative complement cascades. These properties make A␤ an excellent target for microglial phagocytosis, a view supported by multiple reports, through well established mechanisms of phagocyte clearance. GLIA 40:260 -269, 2002.

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Complete or partial spinal section at T(8) has been shown to block tactile allodynia but not thermal hyperalgesia following L(5)/L(6) spinal nerve ligation (SNL), suggesting the supraspinal integration of allodynia in neuropathic pain. In the present study, the possibility of mediation of nerve injury-associated pain through tonic activity of descending nociceptive facilitation arising from the rostroventromedial medulla (RVM) was investigated. Specifically, the actions of brainstem cholecystokinin and the possible importance of sustained afferent input from injured nerve fibers were determined using pharmacological and physiological approaches in rats with SNL. Lidocaine given bilaterally into the RVM blocked tactile allodynia and thermal hyperalgesia in SNL rats and was inactive in sham-operated rats. Bilateral injection of L365,260 (CCK(B) receptor antagonist) into the RVM also reversed both tactile allodynia and thermal hyperalgesia. Microinjection of CCK-8 (s) into the RVM of naive rats produced a robust tactile allodynic effect and a more modest hyperalgesia. CCK immunoreactivity was not significantly different between SNL and sham-operated rats. The anti-nociceptive effect of morphine given into the ventrolateral periaqueductal gray region (PAG) was substantially reduced by SNL. The injection of L365,260 into the RVM or of bupivacaine at the site of nerve injury restored the potency and efficacy of PAG morphine in SNL rats. These results suggest that changes in supraspinal processing are likely to contribute to the observed poor efficacy of opioids in clinical states of neuropathic pain. These data also indicate that the activation of descending nociceptive facilitatory pathways is important in the maintenance of neuropathic pain, appears to be dependent on CCK release, and may be driven from sustained afferent input from injured nerves to brainstem sites. Collectively, these data support the hypothesis that abnormal tonic activity of descending facilitation mechanisms may underlie chronic pain from peripheral nerve injury.

Supraspinally mediated antinociception has been clearly established for agonists acting via both micro- and delta-opioid receptors. The present experiments were undertaken to further characterize the role of supraspinal opioid delta receptors in the mediation of antinociception in rats and to examine the possible role of putative delta1- and delta2-opioid receptors in the antinociceptive effect. Cannulae directed at the right lateral ventricle, the periaqueductal gray (PAG), or the medullary reticular formation (MRF) were implanted in adult male, Sprague-Dawley rats for the microinjection of [D-Ala2,Glu4]deltorphin (delta2 agonist), [D-Pen2,D-Pen5]enkephalin (DPDPE, delta1 agonist), [D-Ser2,Leu5,Thr6]enkephalin (DSLET, mixed delta/micro agonist) or morphine (reference micro-opioid). Pretreatments (24 h prior to agonist microinjection) were made with the putative delta1 and delta2 antagonists, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) and [D-Ala2,Cys4]deltorphin (Cys-DELT) and antinociception was measured in the 55 degrees C hot plate (HP) and 52 degrees C and 55 degrees C (low and high intensity) warm-water tail-flick (TF) tests. Data were converted to percent maximal possible effect (%MPE). Intracerebroventricular (i.c.v.) administration of DPDPE produced less than a 50%MPE in the HP test whereas [d-Ala2,Glu4]deltorphin produced Cys-DELT sensitive antinociception of up to 92% MPE. Neither i.c.v. agonist was effective in the TF assays, and both agonists were without effect in the PAG. [D-Ala2,Glu4]deltorphin microinjected into the MRF produced Cys-DELT sensitive antinociception of 60 and 47% MPE in the HP and low-intensity TF tests, respectively, but was not effective in the 55 degrees C TF test; DPDPE did not produce antinociception when microinjected at this site. Microinjection of DSLET in the MRF produced significant antinociception in all three assays. Morphine produced antinociception following i.c.v. administration or microinjection into the PAG in all tests. Microinjection of morphine into the MRF produced antinociception in the HP and 52 degrees C, but not 55 degrees C, TF tests. Morphine anticociception was not antagonized by either DALCE or Cys-DELT. These data demonstrate that supraspinal delta-opioid receptors can be activated to elicit antinociception in the rat and that opioid delta2 receptors predominate in this effect. Further, these effects may occur predominately via inhibition of supraspinally organized behavior without activation of descending systems such as those mediating the TF response in the rat.

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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.