Anatomical and Pathophysiological Substrates for Neuropathic Pain11
Neuropeptides in Pain Pathways12
Calcitonin Gene-Related Peptide14
Analgesic Actions of Opioids: Presynaptic Mechanisms16
Analgesic Actions of Opioids: Postsynaptic Mechanisms17
The Role of Opioids in Descending Pain Modulation18
CHAPTER 02: LITERATURE REVIEW
This thesis examines aspects of the modulation of pain transmission by spinal neuropeptides. It includes an investigation of the role of neuropeptide Y (NPY) in the modulation of pain signaling in the substantia gelatinosa of the dorsal horn. The interaction of the morphine metabolite, morphine-Sp-Dvglucuronidc (M3G) with spinal pain mechanisms is also examined, as this substance may interact with spinal peptidergic mechanisms. Investigation of the actions of spinal neuropeptides relates to an interest in developing new therapeutic approaches to the treatment of neuropathic pain (Worthylake, 2001, 154). Several cellular mechanisms may account for the development of allodynia and hyperalgesia. These include central sensitization, wind-up and anatomical reorganization of the dorsal horn (Hummel, 1999, 771).
Nociceptive Sensory Fibres
Painful stimuli are detected by a specific class of nerve fibres called nociceptors. Nociceptors can be broadly classified according to their responses to different types of stimuli and the conduction velocity of their axons. Nociceptive primary afferent fibres have restricted receptive fields, are thinly myelinated or unmyelinated fibres and have conduction velocities in the Ao (25- 55m/s) and C-fibre range less tahn2m/s) (Zandy, 2008, 444).
C-fibre mechano-heat nociceptors are thought to be the unmyelinated, slowly conducting fibres (conduction velocity < 2 m/s) that were first described in detail by Perl and colleagues. These receptors are present in the skin and are primarily polymodal nociceptors responding to intense thermal, mechanical and chemical stimuli. Polymodal nociceptors respond to thermal stimuli in the range of 41-49°C and a large proportion of C-fibres are capsaicin-sensitive and express the vanilloid receptor (VRI). Recently, a cold- and menthol-sensitive receptor (CMRI), which may provide a cellular basis for cold sensation, has been identified and is likely present on C-fibres. C-fibres can also be subdivided based on histological markers. The high-affinity tyrosine kinase receptor for nerve growth factor (NGF). These fibres project to lamina I and outer lamina II of the spinal cord. The second group does not express Substance P, CGRP or TrkA, but does express purinergic (P2X3) receptors and is identified by enzymes, such as fluoride-resistant acid phosphatise (Ellezam, 2001, 105).
AD-fibres can be functionally classified into two categories: Type I and Type II. Type I AD fibres typically have conduction velocity in the range of 25-55 rnls and are activated by intense mechanical stimuli or by noxious heat at temperatures above 52°e. Type I receptors were first identified by and are referred to as high-threshold mechanoreceptors. Type II Ao-nociceptors are sensitive to mechanical stimuli and noxious heat, but their temperature threshold is near 43°C, similar to that of C-fibres. Type II AD-fibres also have a lower mean conduction velocity of 15 rnls and respond to ...