We observed that intrathecal (i.t.) bovine adrenal medulla 22, an endogenous opioid peptide, partially reverses morphine tolerance. However, its mechanism remains unclear. The present study determined the effects of BAM8-22, a derivative of BAM22 and selective sensory neuron-specific receptor (SNSR) agonist, on the development and maintenance of tolerance to spinal morphine. Intrathecal administration of BAM8-22 at various doses (0.1, 1 and 10nmol) did not alter withdraw latencies assessed in both paw withdraw and tail flick tests. Co-administration of BAM8-22 (0.1nmol) every other day, but not daily, with morphine remarkably attenuated the development of morphine tolerance. Pretreatment and co-treatment with BAM8-22 (0.1nmol) significantly reversed established morphine tolerance. Furthermore, intermittent administration of BAM8-22 with morphine consistently resumed morphine-induced antinociception. However, i.t. BAM8-22 did not alter morphine-induced hyperalgesia. These results suggested that SNSR may be able to modulate the sensitivity of opioid receptor serving as a most probable underlying mechanism for the effects of BAM8-22 on morphine tolerance. This study also demonstrated that intermittent combination of SNSR agonist BAM8-22 with morphine might be better regimen for long-term use of opioids to treat chronic pain.