Opiate modulation of IL-1alpha, IL-2, and TNF-alpha transport across the blood-brain barrier.

Interleukin-1alpha (IL-1alpha), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-alpha) are proinflammatory cytokines with potent neuromodulatory effects and are implicated in the etiology and pathogenesis of various psychological and neurological disorders. The findings that chronic morphine treatment alters both blood-brain barrier (BBB) function and cytokine production raises the possibility that morphine can also modulate cytokine transport across the BBB. Here, we found that acute morphine treatment (12 mg/kg i.p.) did not alter blood-to-brain transport of IL-1alpha, IL-2 or TNF-alpha. Whereas chronic morphine treatment (48 h after implantation of 75 mg morphine pellets) and withdrawal from morphine (10-15 min after an i.p. injection of 1mg/kg of naltroxone 48 h after implantation of 75 mg morphine pellets) did not alter blood-to-brain transport of IL-1alpha or TNF-alpha, both the chronic morphine treatment and withdrawal from morphine groups had increased blood-to-brain transport of IL-2. Typically, the permeability of the BBB to IL-2 is dominated by brain-to-blood efflux, with only limited blood-to-brain transport. Here, we found that chronic morphine and withdrawal from morphine did not alter brain-to-blood efflux, but induced a novel saturable blood-to-brain transport system. Whereas IL-1alpha, IL-2, and TNF-alpha are all proinflammatory cytokines, morphine exposure has individualized effects on their blood-to-brain transport.