Sensory neuron-specific receptor agonist BAM8-22 inhibits the development and expression of tolerance to morphine in rats

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 10 nmol) did not alter withdraw latencies assessed in both paw withdraw and tail flick tests. Co-administration of BAM8-22 (0.1 nmol) every other day, but not daily, with morphine remarkably attenuated the development of morphine tolerance. Pretreatment and co-treatment with BAM8-22 (0.1 nmol) 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.