Difference between revisions of "Pain Pathophysiology"

====<math>L</math>-type <math>Ca^{2+}</math> Channels====

In the spinal cord, L-type <math>Ca^{2+}</math> channels are expressed by motor neurons and sensory interneurons, where they mediate a slow inward current in response to depolarization and show no significant inactivation. The slow activation and inactivation kinetics lead to plateau potentials. As a result, two different functional states of stability arise in both sensory and motor compartments, one of which is wind-up. Both types of phenomena, similar to wind-up, are voltage-dependent and dihydropyridine-sensitive, involving L-type <math>Ca^{2+}</math> channels. The gradual increase in depolarization in response to repeated current pulses is not due to cumulative depolarization of the membrane potential during the interstimulus interval but to depolarization-induced facilitation of L-type <math>Ca^{2+}</math> channels: this mechanism is known as warm-up. The simplest scheme to explain the warm-up phenomenon is a voltage-dependent transition between two closed states of L-type <math>Ca^{2+}</math> channels: one infrequent state with a high activation threshold and a more frequent state with a lower activation threshold.   

L-type <math>Ca^{2+}</math> channels are regulated by metabotropic receptors: in the sensory compartment, they are positively regulated by GLUT and SP and negatively by GABAB. These modulators contribute to the dynamic regulation of excitability and the intrinsic characteristics of plateau currents <ref>Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001 Oct; 429: 23-37</ref>.

Some data suggest that, in chronic pain, specific genes involved in apoptosis are active, contributing to critical changes in cell survival and the establishment of chronic pain states <ref>Ham J, Babij C, Whitfield J. Activation of c-Jun N-terminal kinase in dorsal root ganglion neurons following axotomy. J Neurosci 1997; 17: 6464-6472.</ref>.   

Following axonal injury, some neurons in the dorsal root ganglia undergo apoptosis, resulting in deafferentation of postsynaptic spinal neurons. These in turn degenerate due to the lack of tonic inhibitory stimulation of apoptosis normally exerted by the presynaptic neuron. The preventive administration of MK-801, a competitive NMDAR antagonist, prevents cell death due to axotomy in nearly all cases <ref>Lopez-Garcia JA, King AE. Neuronal cell death after peripheral nerve injury and the role of NMDAR activation. J Neurosci 1997; 17: 4325-4332.</ref>.   

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