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

Interleukin-1α (IL-1α), interleukin-2 (IL-2), and tumor necrosis factor α (TNF-α) 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-1α, IL-2 or TNF-α. 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 1 mg/kg of naltroxone 48 h after implantation of 75 mg morphine pellets) did not alter blood-to-brain transport of IL-1α or TNF-α, 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-1α, IL-2, and TNF-α are all proinflammatory cytokines, morphine exposure has individualized effects on their blood-to-brain transport.