Oxytocin reduces excitability of sensory afferents
Abstract Number: 70
Abstract Type: Case Report/Case Series
Spinal opioids, commonly used to treat labor and post-cesarean delivery pain, act primarily on the central terminals of sensory afferents in the spinal cord. Clinical and laboratory data suggest that spinally released oxytocin, while not reducing the pain of labor, reduces the risk of chronic pain from tissue injury during childbirth. Here we tested whether oxytocin targets central terminals of sensory afferents in the spinal cord to produce this effect.
Following ACUC approval, in vitro and in vivo studies were performed in rats. In vitro, sensory neurons from the dorsal root ganglia were acutely dissociated, cultured, and loaded with a fluorescent dye to measure intracellular Ca++ concentration. In vivo, single dorsal root ganglion cells were impaled, intracellular recordings obtained, and membrane properties recorded using standard electrophysiologic protocols.
In vitro study of 563 small to medium diameter dorsal root ganglion cells revealed a dose related, small (< 10 nM) increase in intracellular Ca++ in response to oxytocin, with a threshold of 100 nM. In contrast to this small direct increase, oxytocin produced a large reduction in KCl stimulated increase in intracellular Ca++, with a threshold of 10 nM and with over 70% of cells inhibited at 1 microM oxytocin. Both effects (minor direct excitation and profound reduction in response to depolarization) were inhibited by administration of a selective oxytocin receptor antagonist.
In vivo study of large diameter dorsal root ganglion cells identified by low threshold mechano-receptors (LTMRs) which were sensitive to light touch and A-fiber high threshold mechano-receptors (A-HTMRs) which responded to intense stimuli in the nociceptive range. Perfusion with oxytocin, 1 microM led to minimal effects in LTMRs. In contrast, the amount of current required to induce action potentials (rheobase) was reduced by nearly 50% in A-HTMRs, a sign of excitability. This effect was counterbalanced, however, by a prolonged refractory period, with the net result being a nearly 35% reduction in the number of action potentials in response to a sustained depolarization stimulus.
Spinal opioids act primarily by inhibiting responses of small diameter, C-neurons in the spinal cord, with little effect on larger diameter mechano-sensitive afferents responsible for proprioception. Our results suggest the effect of oxytocin is much subtler, with partial inhibition of C-neurons, perhaps by a mechanism involving primary afferent depolarization, and a reduction in sustained input from mechano-sensitive nociceptors. These subtle effects could explain the lack of efficacy of intrathecal oxytocin against labor pain, but its protection against hypersensitivity after nerve injury.
Supported in part by NIH grant GM48085