Clostridial toxin derivatives able to modify peripheral sensory

Details Clostridial toxin derivatives able to modify peripheral sensory Clostridial toxin derivatives able to modify peripheral sensory

1998-01-12

1999-11-23

Mosher, Mary E.

Drug, bio-affecting and body treating compositions

Conjugate or complex of monoclonal or polyclonal antibody,...

Conjugated to proteinaceous toxin or fragment thereof

424 9467, 424832, 514 2, 53038822, 5303917, 530350, 530402, 435 691, 435 697, 435220, A61K 3816, C07K 1433, C07K 1900, C12N 1562

Patent

active

059895454

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a novel agent that is able to modify peripheral afferent function. The agent may inhibit neurotransmitter release from discrete populations of neurons, and thereby reduce, or preferably prevent, the transmission of afferent pain signals from peripheral to central pain fibres. The agent may be used in or as a pharmaceutical for the treatment of pain, particularly chronic pain.


BACKGROUND

The sense of touch has traditionally been regarded as one of the five classical senses, but in reality it is highly complex, transducing a number of different sensations. These sensations are detected in the periphery by a variety of specialised nerve endings and associated structures. Some of these are specific for mechanical stimuli of various sorts such as touch, pressure, vibration, and the deformation of hairs or whiskers. Another class of nerves is able to detect temperatures, with different fibres being activated by heat and cold. A further population of nerve endings is not normally excited by mild stimuli, but by strong stimuli only. Sensory nerves of this category often respond to more than one stimulus, and are known as high-threshold polymodal fibres. They may be used to sense potentially damaging situations or objects. The polymodal fibres also transduce chemical signals such as the "burning" sensation evoked by acid. Thus, the sense of touch can transmit a very detailed description of objects and serve to both inform and warn of events.
The transduction of sensory signals from the periphery to sensation itself is achieved by a multi-neuronal pathway and the information processing centres of the brain. The first nerve cells of the pathway involved in the transmission of sensory stimuli are called primary sensory afferents. The cell bodies for the primary sensory afferents from the head and some of the internal organs reside in various of the ganglia associated with the cranial nerves, particularly the trigeminal nuclei and the nucleus of the solitary tract. The cell bodies for the primary sensory afferents for the remainder of the body lie in the dorsal root ganglia of the spinal column. The primary sensory afferents and their processes have been classified histologically; the cell bodies fall into two classes: A-type are large (60-120 .mu.m in diameter) while B-type are smaller (14-30 .mu.m) and more numerous. Similarly the processes fall into two categories: C-fibres lack the myelin sheath that A-fibres possess. A-fibres can be further sub-divided into A.beta.-fibres, that are large diameter with well developed myelin, and A.delta.-fibres, that are thinner with less well developed myelin. It is generally believed that A.beta.-fibres arise from A-type cell bodies and that A.delta.- and C-fibres arise from B-type cell bodies. These classifications can be further extended and subdivided by studying the selective expression of a range of molecular markers.
Functional analyses indicate that under normal circumstances A.beta.-fibres transmit the senses of touch and moderate temperature discrimination, whereas the C-fibres are mainly equivalent to the polymodal high-threshold fibres mentioned above. The role of A.delta.-fibres is less clear as they seem to have a variety of responsive modes, with both high and low thresholds.
After the activation of the primary sensory afferents the next step in the transduction of sensory signals is the activation of the projection neurons, which carry the signal to higher parts of the central nervous system such as the thalamic nuclei. The cell bodies of these neurons (other than those related to the cranial nerves) are located in the dorsal horn of the spinal cord. This is also where the synapses between the primary afferents and the projection neurons are located. The dorsal horn is organised into a series of laminae that are stacked, with lamina I being most dorsal followed by lamina II, etc. The different classes of primary afferents make synapses in different laminae. For cutaneous primary afferents, C-fibres make synapses in lami

REFERENCES:
patent: 5614488 (1997-03-01), Bacha
Montecucco et al. Q. Rev. Biophys. 28:423-72, abstracts only cited, Nov. 1995.
Halpern, J.L. et al. Journal of Biological Chemistry 268(15):11188-11192, 1993.

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