Epinephrine inhibits analgesic tolerance to intrathecal administrated morphine and increases the expression of calcium-calmodulin-dependent protein kinase IIalpha.

Activation of hypothalamic-pituitary-adrenal (HPA) axis inhibits development of morphine tolerance. Also, the expression of CaMKIIalpha is increased following chronic administration of morphine. In the current study, we tried to examine the effect of epinephrine, on the development of morphine tolerance; and also evaluate the expression of CaMKIIalpha as a molecular index for tolerance development. Analgesic tolerance was induced by intrathecal (i.t.) injection of morphine 15 microg/rat, twice a day for 5 days. To study the effect of epinephrine on development or reversal of morphine tolerance, epinephrine was administrated 20 min before morphine injections. Analgesia was assessed using tail flick test. Gene expression assays were done using RT-PCR. Following 5 days of combined administration of morphine and epinephrine (2, 5 or 10 microg/rat), in day 6, morphine produced potent analgesia. Administration of saline and morphine during days 1-5, caused reduced analgesic effect of morphine on day 6. After tolerance induction during 5 days, co-administration of epinephrine and morphine for another 5 days, significantly reversed the tolerance. Both morphine and epinephrine increased the expression of CaMKIIalpha. The expression of CaMKIIalpha was highly increased following combined administration of epinephrine and morphine. Our results showed the inhibition and reversal of analgesic tolerance to local administrated morphine by epinephrine. We observed the increased expression of CaMKIIalpha without development of morphine tolerance in animals treated with combined epinephrine and morphine.