Hyperalgesia and allodynia are frequent symptoms of disease and may be useful adaptations to protect vulnerable tissues. Both may, however, also emerge as diseases in their own right. Considerable ...

/pdf/models-and-mechanisms-of-hyperalgesia-and-allodynia-22ddij4jlr.pdf

Models and Mechanisms of Hyperalgesia and Allodynia

Chronic pain is a major challenge to clinical practice and basic science. The peripheral and central neural networks that mediate nociception show extensive plasticity in pathological disease states. Disease-induced plasticity can occur at both structural and functional levels and is manifest as changes in individual molecules, synapses, cellular function and network activity. Recent work has yielded a better understanding of communication within the neural matrix of physiological pain and has also brought important advances in concepts of injury-induced hyperalgesia and tactile allodynia and how these might contribute to the complex, multidimensional state of chronic pain. This review focuses on the molecular determinants of network plasticity in the central nervous system (CNS) and discusses their relevance to the development of new therapeutic approaches.

Central mechanisms of pathological pain

Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel- and vehicle-treated rats were perfused on days 7, 27 and 160. Portions of saphenous nerves were processed for electron microscopy. There was no evidence of paclitaxel-induced degeneration or regeneration as myelin structure was normal and the number/density of myelinated axons and C-fibres was unaltered by paclitaxel treatment at any time point. In addition, the prevalence of ATF3-positive dorsal root ganglia cells was normal in paclitaxel-treated animals. With one exception, at day 160 in myelinated axons, total microtubule densities were also unaffected by paclitaxel both in C-fibres and myelinated axons. C-fibres were significantly swollen following paclitaxel at days 7 and 27 compared to vehicle. The most striking finding was significant increases in the prevalence of atypical (swollen and vacuolated) mitochondria in both C-fibres (1.6- to 2.3-fold) and myelinated axons (2.4- to 2.6-fold) of paclitaxel-treated nerves at days 7 and 27. Comparable to the pain behaviour, these mitochondrial changes had resolved by day 160. Our data do not support a causal role for axonal degeneration or dysfunction of axonal microtubules in paclitaxel-induced pain. Instead, our data suggest that a paclitaxel-induced abnormality in axonal mitochondria of sensory nerves contributes to paclitaxel-induced pain.

/pdf/studies-of-peripheral-sensory-nerves-in-paclitaxel-induced-6r5342xi9p.pdf

Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction.

http://www-3.unipv.it/dsffcm/pagine/labs/perin/oldstuff/kiro/stressimmune.pdf

Pain and stress in a systems perspective: reciprocal neural, endocrine, and immune interactions.

The structure and function of the skin details the individual components of the epidermis, dermis, and their roles in normal skin health. The individual cell types in the epidermis, the different epidermal layers, and the roles of the keratinocyte are explained. The epidermis and dermis, and their important relation to each other through the dermoepidermal junction are described. The dermal adnexal structures of hair follicles (pilosebaceous units), sweat glands, and nerves are all considered. The functions of skin and barrier function are also listed. Rare but important causes of disordered sweating (hyperhidrosis and hypohidrosis) are described. In addition, presentations of hyperhidrosis are discussed.

Structure and function of the skin

Paclitaxel- and vincristine-evoked painful peripheral neuropathies: Loss of epidermal innervation and activation of Langerhans cells

Paclitaxel and vincristine are chemotherapeutic drugs that often evoke a long-lasting painful peripheral neuropathy. Using drugs that reduce intracellular or extracellular calcium ions (Ca2+), we investigated the hypothesis that impaired Ca2+ regulation contributes to the chemotherapy-evoked neuropathic pain syndrome. For comparison, we also tested rats with painful peripheral neuropathy caused by nerve trauma and to the anti-human immunodeficiency virus nucleoside analog 2',3'-dideoxycytidine (ddC). Normal naive (without neuropathy), paclitaxel-treated, and vincristine-treated rats received the following intrathecal injections: TMB-8 (46 nmol), Quin-2 (1.8 nmol), EGTA (0.1 micromol), EGTA-am (0.1 micromol), and their vehicle controls. Chronic constriction injury (CCI) rats were examined after TMB-8 and Quin-2 injections, and ddC-treated rats were examined after receiving TMB-8. Mechano-allodynia and mechano-hyperalgesia were evaluated after each injection. Drug effects on heat hyperalgesia were also tested in CCI rats. All four Ca2+-reducing drugs significantly inhibited mechano-allodynia and mechano-hyperalgesia in the rats treated with paclitaxel, vincristine, or ddC, but no effects were seen in the CCI or naive rats. We conclude that a similar abnormality of cellular Ca2+ homeostasis contributes to the pain caused by paclitaxel, vincristine, and ddC, but not posttraumatic painful peripheral neuropathy.

/pdf/dysregulation-of-cellular-calcium-homeostasis-in-ydd0yhzplu.pdf

Dysregulation of cellular calcium homeostasis in chemotherapy-evoked painful peripheral neuropathy

The antineoplastic agent paclitaxel causes a dose-limiting distal, symmetrical, sensory peripheral neuropathy that is often accompanied by a neuropathic pain syndrome. In a low-dose model of paclitaxel-evoked painful peripheral neuropathy in the rat, we have shown that the drug causes degeneration of intraepidermal nerve fibers (IENFs), i.e. the fibers which give rise to the sensory afferent's terminal receptor arbor. However, we did not find any evidence for axonal degeneration in samples taken at the mid-nerve level. Here we aimed to determine whether the absence of degenerating peripheral nerve axons was due to sampling a level that was too proximal. We used electron microscopy to study the distal-most branches of the nerves innervating the hind paw glabrous skin of normal and paclitaxel-treated rats. We confirmed that we sampled at a time when IENF degeneration was prominent. Because degeneration might be easier to detect with higher paclitaxel doses, we examined a four-fold cumulative dose range (8-32 mg/kg). We found no evidence of degeneration in the superficial subepidermal axon bundles (sSAB) that are located just a few microns below the epidermal basal lamina. Specifically, for all three dose groups there was no change in the number of sSAB per millimeter of epidermal border, no change in the number of axons per sSAB and no change in the diameter of sSAB axons. We conclude that paclitaxel produces a novel type of lesion that is restricted to the afferent axon's terminal arbor; we name this lesion 'terminal arbor degeneration'.

/pdf/terminal-arbor-degeneration-a-novel-lesion-produced-by-the-4tlvl986ho.pdf

Terminal arbor degeneration--a novel lesion produced by the antineoplastic agent paclitaxel.

Background
Cutaneous tactile allodynia, or painful hypersensitivity to mechanical stimulation of the skin, is typically associated with neuropathic pain, although also present in chronic pain patients who do not have evidence of nerve injury. We examine whether deep tissue microvascular dysfunction, a feature common in chronic non-neuropathic pain, contributes to allodynia.

https://repub.eur.nl/pub/14228/18957097.pdf

Chiang Siau

Papers

Paclitaxel- and vincristine-evoked painful peripheral neuropathies: Loss of epidermal innervation and activation of Langerhans cells

Dysregulation of cellular calcium homeostasis in chemotherapy-evoked painful peripheral neuropathy

Terminal arbor degeneration--a novel lesion produced by the antineoplastic agent paclitaxel.

Cutaneous tactile allodynia associated with microvascular dysfunction in muscle.

Characterization of a model of cutaneous inflammatory pain produced by an ultraviolet irradiation-evoked sterile injury in the rat