Axonal rejoining inhibits injury-induced long-term changes in Aplysia sensory neurons in vitro.

Injury of Aplysia sensory neurons, both in the CNS and in dissociated cell culture, produces long-term changes in these cells, among which are hyperexcitability and enhanced neuritic outgrowth (hypermorphogenesis). These long-term, injury-induced changes are attributable, in part, to the generation of new intrinsic cellular signals. Little is known, however, about the signals that maintain homeostasis within sensory neurons. To elucidate the role of homeostatic signals in Aplysia sensory neurons, we investigated how axonal rejoining alters the cellular consequences of axotomy. Sensory neurons in dissociated cell culture were axotomized. In some cases, the distal segment of the severed axon was then removed; in other cases, the proximal and distal segments of the severed axon were permitted to rejoin. If the severed distal segment was left unmolested, then axonal rejoining invariably occurred within 7 hr. Surprisingly, we found that the characteristic long-term cellular consequences of axotomy were suppressed by axonal rejoining. The long-term axotomy-induced changes were not inhibited merely by contact between the severed axon and another, uninjured sensory neuron. These results indicate that long-term changes in sensory neurons induced by injury are attributable, in part, to prolonged disruption of a retrograde homeostatic signal that originates in the distal segment of the growing neurite and chronically suppresses hyperexcitability and hypermorphogenesis.

Long-term effects of axotomy on excitability and growth of isolated Aplysia sensory neurons in cell culture: potential role of cAMP.

Crushing nerves, which contain the axons of central sensory neurons, in Aplysia causes the neurons to become hyperexcitable and to sprout new processes. Previous experiments that examined the effects of axonal injury on Aplysia sensory neurons have been performed in the intact animal or in the semi-intact CNS of Aplysia. It therefore has been unclear to what extent the long-term neuronal consequences of injury are due to intrinsic or extrinsic cellular signals. To determine whether injury-induced changes in Aplysia sensory neurons are due to intrinsic or extrinsic signals, we have developed an in vitro model of axonal injury. Isolated central sensory neurons grown for 2 days in cell culture were axotomized. Approximately 24 h after axotomy, sensory neurons exhibited a greater excitability-reflected, in part, as a significant reduction in spike accommodation-and greater neuritic outgrowth than did control (unaxotomized) neurons. Rp diastereoisomer of the cyclic adenosine 3',5'-monophosphorothiate (Rp-cAMPS), an inhibitor of protein kinase A, blocked both the reduction in accommodation and increased neuritic outgrowth induced by axotomy. Rp-cAMPS also blocked similar, albeit smaller, alterations observed in control sensory neurons during the 24-h period of our experiments. These results indicate that axonal injury elevates cAMP levels within Aplysia sensory neurons, and that this elevation is directly responsible, in part, for the previously described long-term electrophysiological and morphological changes induced in Aplysia sensory neurons by nerve crush. In addition, the results indicate that control sensory neurons in culture are also undergoing injury-related electrophysiological and structural changes, probably due to cellular processes triggered when the neurons are axotomized during cell culturing. Finally, the results provide support for the idea that the cellular processes activated within Aplysia sensory neurons by injury, and those activated during long-term behavioral sensitization, overlap significantly.

Fenclofenac and diclofenac in the treatment of rheumatoid arthritis.

A six-month single-blind, randomized parallel group study comparing the effects of fenclofenac and diclofenac in 63 patients with rheumatoid arthritis is described. Both treatments produced improvements in clinical measurements, with a significant between-treatment effect in favour of fenclofenac for overall pain, night pain and duration of morning stiffness. Both treatments produced a decrease in IgM and the fenclofenac group produced decreases in plasma viscosity and ESR, the latter showing a significant between-treatment effect in favour of fenclofenac. No clinically significant changes in routine haematology and biochemistry were noted. Unwanted effects leading to withdrawal of therapy were reported by five patients in the fenclofenac group and three patients in the diclofenac group. Two patients in the fenclofenac group and one in the diclofenac group were withdrawn for reasons unrelated to therapy. In the diclofenac group two and four patients were withdrawn for clinical deterioration and inadequate effect respectively.

Double-blind comparison of alclofenac and aspirin in the treatment of rheumatoid arthritis. Part II: high dosage regime for assessment of analgesic and anti-inflammatory activity.

A double-blind trial was carried out in 76 patients with active rheumatoid arthritis to compare the analgesic and anti-inflammatory activity of 3 g. alclofenac with 4.8 g. aspirin daily over a 6-week period. All patients selected showed reversible inflammatory swelling of the finger joints. Of the 60 patients successfully completing the trial, 30 were treated as out-patients and 30 patients received in-patient treatment for approximately the first 2 weeks. Both groups were analysed separately. Treatment was randomised and patients received the drugs in identical tablet form except for the last 16 patients who were transferred to capsules. Results showed that though the activity potential, morning stiffness, grip strength, joint pain and tenderness improved significantly at the end of the 6-week period, there was no statistical difference between the two drugs. However, functional capacity indicated slight superiority of alclofenac over aspirin at a low level of significance. P.I.P. joint swelling showed that both in-patients and out-patients on alclofenac improved significantly (p less than .001)compared to patients in the aspirin group. Laboratory investigations showed no difference between the two drugs as far as changes in serum proteins, serum transaminase, haemoglobin and E.S.R. levels were concerned. However, serum uric acid levels dropped significantly (.05 greater than p greater than .01) with aspirin. The incidence of side-effects was slightly higher in the aspirin group but a high incidence of skin rash (30% approx.) was recorded with alclofenac tablets. No incidence of skin rash was recorded in patients taking alclofenac capsules, but the number of patients taking capsules was too small to make any prediction. It appears from this study that in active rheumatoid arthritis the analgesic and anti-inflammatory activity of 3 g. alclofenac is equivalent to 4.8 g. aspirin, and alclofenac is superior to aspirin in reducing the inflammatory swelling of rheumatoid joints.