Dual effects of intrathecal BAM22 on nociceptive responses in acute and persistent pain--potential function of a novel receptor.

Bovine adrenal medulla 22 (BAM22) peptide is one of the cleavage products of proenkephalin A. It binds with high affinity to both opioid receptors and a newly discovered receptor in vitro. This latter receptor was first named sensory neuron-specific receptor and is here named BAM peptide-activated receptor with non-opioid activity (BPAR). BPAR is uniquely distributed in small-diameter DRG neurons, most of which are associated with the IB4 class of nociceptor afferent. The present study examined the effects of intrathecal administration of BAM22 on formalin-induced nocifensive behaviors and tail-withdrawal latency in the rat. Intrathecal (i.t.) administration of BAM22 decreased nocifensive behavior scores, measured as the sum of flinching and lifting/licking, in the first and second phases of the formalin test. This decrease was partially attenuated by systemic injection of naloxone. In the presence of naloxone, i.t. BAM22 produced a dose-dependent suppression of the nocifensive behaviors observed during the formalin test. The ratio of the efficacy of BAM22 (5 nmol) in the presence of naloxone over that in the absence of naloxone was 0.65 for flinching and 0.74 for lifting/licking in the second phase. BAM22 at a dose of 5 nmol increased the tail-withdrawal latency by 193 and 119% of baseline in the absence and presence of naloxone, respectively. Systemic administration of naloxone alone enhanced the nocifensive behaviors in the second, but not in the first phase of the formalin test. Naloxone treatment did not alter the tail-withdrawal latency. These data confirm earlier in vitro data showing that BAM22 has both opioid and non-opioid biological actions. The non-opioid action of BAM22 involves inhibition of acute and persistent nociceptive behaviors at the spinal level, presumably mediated via BPAR. The name suggested for this novel receptor, its potential physiological function and its ligand are discussed. British Journal of Pharmacology (2004) 141, 423-430. doi:10.1038/sj.bjp.0705637