Modulation of sensory neuron-specific receptors in the development of morphine tolerance and its neurochemical mechanisms.

Prevention of opiate tolerance is a critical issue in pain management. The present study was designed to characterize the pharmacological properties of sensory neuron-specific receptors (SNSR; also known as Mas-related gene receptors, or Mrg) for their modulation in the development of morphine tolerance and to investigate the underlying mechanism(s). Daily coadministration of the SNSR agonist BAM8-22 at a dose of 0.01 or 0.001, but not 1.0, nmol with morphine (intrathecally, or i.t., 20 microg/day) for 6 days significantly decreased the development of morphine tolerance. Coadministration of BAM8-22 (i.t., 1.0 nmol) on days 1, 3, and 5 completely blocked tolerance to morphine-induced analgesia. Intermittent coadministration of the structurally dissimilar SNSR agonist (Tyr(6))-2-MSH-6-12 (MSH; 5 nmol) also produced similar modulation. Chronic administration of morphine (20 microg, i.t.) increased expression of neuronal nitric oxide synthase (nNOS) and calcitonin gene-related peptide (CGRP) in superficial layers of the spinal cord and dorsal root ganglia. All these increases were abolished when BAM8-22 or MSH was intermittently coadministered. Furthermore, intermittent administration of BAM8-22 inhibited morphine-induced increase in protein kinase C gamma (PKC gamma) in both membrane and cytosol of spinal dorsal horn neurons. These results suggest that moderate activation of SNSR modulated morphine tolerance by inhibition of the PKC signaling pathway, leading to abolishment of enhancement of nNOS and CGRP. As SNSR are uniquely located ina subset of small-sized neurons in dorsal root and trigeminal ganglia, intermittent combination of SNSR agonist could be a promising adjunct for sustained use of opiates without central nervous system side effects.