1 To gain further insight into the mechanisms underlying the antihyperalgesic and antiallodynic actions of gabapentin, a chronic pain model was prepared by partially ligating the sciatic nerve in mice. The mice then received systemic or local injections of gabapentin combined with either central noradrenaline (NA) depletion by 6-hydroxydopamine (6-OHDA) or a-adrenergic receptor blockade. 2 Intraperitoneally (i.p.) administered gabapentin produced antihyperalgesic and antiallodynic effects that were manifested by elevation of the withdrawal threshold to a thermal (plantar test) or mechanical (von Frey test) stimulus, respectively. 3 Similar effects were obtained in both the plantar and von Frey tests when gabapentin was injected intracerebroventricularly (i.c.v.) or intrathecally (i.t.), suggesting that it acts at both supraspinal and spinal loci. This novel supraspinal analgesic action of gabapentin was only obtained in ligated neuropathic mice, and gabapentin (i.p. and i.c.v.) did not affect acute thermal and mechanical nociception. 4 In mice in which central NA levels were depleted by 6-OHDA, the antihyperalgesic and antiallodynic effects of i.p. and i.c.v. gabapentin were strongly suppressed. 5 The antihyperalgesic and antiallodynic effects of systemic gabapentin were reduced by both systemic and i.t. administration of yohimbine, an a 2 -adrenergic receptor antagonist. By contrast, prazosin (i.p. or i.t.), an a 1 -adrenergic receptor antagonist, did not alter the effects of gabapentin. 6 It was concluded that the antihyperalgesic and antiallodynic effects of gabapentin are mediated substantially by the descending noradrenergic system, resulting in the activation of spinal a 2 -adrenergic receptors.

IL-1 receptor antagonist (IL-1ra) is a cytokine that competitively binds the IL-1 receptor to antagonize IL-1 activity without any agonist function. Previous experiments indicated that the ratio of IL-1ra to IL-1alpha in the normal stratum corneum (SC) was much higher in the sun-exposed face than in the sun-protected area, upper arms. It was also reported by another laboratory that IL-1ra is increased in the lesional skin of psoriatic patients. This study was designed to measure the contents of IL-1alpha and IL-1ra in non-lesional and pathological SC obtained from inflammatory skin diseases including psoriasis and non-psoriatic dermatoses such as atopic dermatitis. The SC materials were obtained with a non-invasive tape-stripping method. Their soluble fractions were prepared and assayed for IL-1alpha and IL-1ra by enzyme-linked immunosorbent assays. As a result we confirmed the previous findings that the ratio of IL-1ra to IL-1alpha in the normal SC was much higher in the face than in the sun-protected sites, the trunk as well as extremities. Next, we found that IL-1alpha contents were significantly reduced in the SC samples obtained from inflammatory skin regardless of whether their IL-1ra contents increased or unchanged. Moreover, we noted that an increased ratio of IL-1ra to IL-1alpha in the SC was not specific to psoriasis, but was also found in other inflammatory skin diseases including atopic dermatitis. This ratio was found to become lower after successful treatment of these skin lesions with topical glucocorticoids. We conclude from these observations that the increased ratio of IL-1ra to IL-1alpha in the SC is a non-specific phenomenon that can occur in any inflammatory skin diseases regardless of the inflammatory pattern, probably reflecting a skin regulation process against various kinds of inflammation.

No abstract

To evaluate the association of alleles of regions having regulatory potential in the IL-6 gene, with SLE, the AT-rich minisatellite in the 3Ј flanking region and the 5Ј promoter-enhancer of the IL-6 gene were genotyped by PCR-and RFLPbased methods. The AT-rich minisatellite allele distribution pattern was significantly different in SLE (n = 146) as compared to 139 controls ( 2 7 = 48.97, P = 0.001, Caucasians; and 2 7 =19.93, P = 0.006, African-Americans). In either race, short allele sizes (р792 bp) were seen exclusively in SLE patients (P = 0.001), whereas the 828-bp allele was overrepresented in controls (P = 0.015 and 0.002). In contrast, there was no preferential association of SLE with G/C alleles in the 5Ј region of the IL-6 gene. Furthermore, our results suggest that the 3Ј minisatellite alleles have biological significance: (1) B lymphoblastoid cells of patients having one or two SLE-associated alleles secreted IL-6 in 3-to 4-fold higher levels than non-allelic cells (P Ͻ 0.05); (2) higher percentages (approximately 4-fold) of IL-6 positive monocytes were observed in individuals having SLE-associated IL-6 alleles; (3) in lupus patients having SLE-associated minisatellite alleles, IL-6 mRNA stability was significantly enhanced.