Objective: Considering the inhibitory effect of integrin-activity modulator (manganese) on the development of morphine tolerance; in this study we have tried to assess the effect of chronic administration of both morphine and manganese on the expression levels of β1 and β2 integrins in the dorsal horn of the lumbar spinal cord. Materials and Methods: Morphine tolerance was induced by intrathecal injection of morphine 15 μg/rat twice a day for five days. In order to study the effect of manganese on tolerance development; we injected manganese alone or in combination with morphine. The analgesic effect of morphine was assessed by using the tail flick test. Semi-quantitative reverse tranh1ion - polymerase chain reaction (RT-PCR) was used to assess the expression levels of β1 and β2 integrins. Results: As assessed on day 6 five days administration of morphine significantly increased the expression levels of integrins β1 and β2. Combined administration of morphine and manganese which inhibited morphine tolerance prevented the effect of morphine on integrins’ expression. Conclusion: Increased expression of integrins may be due to direct effect of chronic morphine or a negative feedback that resulted from the potent inhibitory effect of morphine on integrins’ activity. It seems that the activating of integrins via manganese in the presence of morphine can reverse feedback and consequently the effect of chronic administration of morphine on β1 and β2 integrins’ and expression. Our findings suggest a role for intracellular matrix molecules in the development of morphine tolerance and possibly other forms of synaptic plasticity.