Control Of Pain Processing Research Articles

The heparin binding growth factors midkine and pleiotrophin regulate the antinociceptive effects of morphine through α2-adrenergic independent mechanisms

Genetic deletion of pleiotrophin (PTN) impairs spinal nociceptive transmission suggesting that this heparin binding growth factor could play roles in acute pain processing. Despite the high functional redundancy between PTN and midkine (MK), the only other member of this family of growth factors, we now demonstrate that genetic inactivation of MK does not alter acute nociceptive transmission since pain responses of female MK genetically deficient (MK−/−) and wild type (WT+/+) mice were found to be similar in the hot-plate and tail-immersion tests. It has also been shown that morphine administration significantly regulates MK levels within the brain, suggesting that MK could play a role in morphine-induced antinociceptive effects. To test this hypothesis, we have now studied morphine-induced antinociceptive effects in female MK−/− and WT+/+ mice. We did not find differences among genotypes using different doses of morphine (2.5, 5 and 10mg/kg) in the hot-plate test. In contrast, we found that morphine significantly delayed pain responses in MK−/− mice compared to WT+/+ mice in the tail-immersion test. In confirmation of previous results from our group, we also found significantly enhanced morphine-induced antinociceptive effects in PTN−/− mice in the tail-immersion test. In addition, we now demonstrate that enhanced morphine analgesic effects in PTN−/− and MK−/− mice are not caused by a different contribution of descending noradrenergic inhibitory pathways since the α2-adrenergic antagonist yohimbine failed to alter morphine-induced analgesia in all genotypes. The data demonstrate that MK is an endogenous modulator of morphine antinociceptive effects, identify significant differences between PTN and MK in the control of pain processing at the spinal level, and support the hypothesis that inhibitors of the PTN/MK signaling pathway could potentiate opioid analgesia which may be relevant in opioid-refractory pain cases.

Immunohistochemical localization of the carboxy terminus of the novel mu opioid receptor splice variant MOR-IC within the human spinal cord

The present study examined the distribution in the human spinal cord of a unique carboxy terminus sequence contained within MOR-1C, one of the recently described splice variants of the cloned mu opioid receptor gene MOR-1. Although MOR-1-like immunoreactivity (LI) and delta opioid receptor-like immunoreactivity were observed only in the superficial laminae, MOR-1C-LI was abundant in the superficial laminae of the dorsal horn and around the central canal. In the substantia gelatinosa, MOR-1C-LI was found in small diameter axonal elements, the cytoplasm and the plasmalemma of small spinal neurons and dendrites in inner lamina II and in some fibers within Lissauer's tract. These studies imply the presence of MOR-1C in human spinal cord and its distribution suggests that it plays a role in the control of pain processing.

Efferent projections from the subnucleus reticularis dorsalis (SRD): A Phaseolus vulgaris leucoagglutinin study in the rat

Small iontophoretic applications of Phaseolus vulgaris leucoagglutinin (PHA-L) were used in rats to study the efferent projections from a restricted region in the reticular formation of the caudal medulla: the subnucleus reticularis dorsalis (SRD). It was found that fibres from SRD project mainly to the spinal cord, the oral motor nuclei, the dorsal accessory inferior olive, the giganto- and parvo-cellular nuclei of the reticular formation and the parafascicular and ventromedian nuclei of the thalamus. Together with our previous electrophysiological findings, this study suggests that the SRD could be involved both in the control of pain processing and in motor reactions elicited by noxious events.