Analgesic and antinociceptive methods

Details Analgesic and antinociceptive methods Analgesic and antinociceptive methods

1999-06-07

2002-09-17

Lankford, Jr., Leon B. (Department: 1651)

Drug, bio-affecting and body treating compositions

Topical body preparation containing solid synthetic organic...

C424S078020, C424S078060, C424S078050, C424S484000, C424S485000

Reexamination Certificate

active

06451301

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to analgesic and antinociceptive methods.
BACKGROUND OF THE INVENTION
Peripheral nociceptors are neurons primarily responsible for responding to noxious stimuli giving rise to pain. Most nociceptors are non-myelinated C-fibers, and they are among the smallest diameter of mammalian neurons (see, e.g., Chapter 48 in
Textbook of Medical Physiology
, 7
th
Ed., Guyton, (W. B. Saunders, Co., 1986)). C-fibers are peptidergic neurons releasing tachykinins (notably Substance P and neurokinins), calcitonin gene-related peptide (CGRP), and other neuroactive peptides. The peripheral nociceptor termini (the neurites responsible for initial transduction of noxious stimulus), lie throughout the body in cutaneous, subcutaneous and visceral organs and tissues (Dubner et al.,
Ann. Rev. Neurosci
., 6, 381-418 (1983); Coggshall et al.,
Brain Res
., 272, 185-88 (1983)). Generally, the peripheral termini of nociceptors are loosely arrayed into networks of neurites able to interact with each other as well as react to endogenous and exogenous environmental noxious stimuli. Such networks represent the branched termini of neurites lying within nerves whose somas are within the paired dorsal root ganglia (DRG) lying to each side of the spinal column in a semisegmental array. Afferent nociceptor neurites run from the DRG to innervate the spinal substantia gelatinosa. Generally, spinal nociceptive innervation is via synapses with projection neurons ascending into the contralateral spinothalamic tract, through the thalamus, and ultimately to the cerebral cortex (Fields, 479-86 in
Advances in Pain Research and Therapy
, Fields et al., eds. (Raven Press, New York, 1985); Jessell et al., 384-99 in
Principles of Neural Science
, 3d. ed., Kandel et al., eds. (Elsevier, New York, 1991)).
Nociceptive neurons play a dual role in the transduction of noxious stimuli. In one mode, nociceptors mediate local physiological response to such stimuli. Roughly 90% of the substance P produced in nociceptor somas is transported to the peripheral nociceptor termini (Levine et al.,
J. Immunol
., 135, 843S-47S (1995); Brimjoin et al.,
Brain Res
., 191, 443 (1986)). Upon stimulation, the peripheral nociceptor termini release peptide agents, which mediate a number of physiological responses locally. Peripherally-released substance P and CGRP cause vasodilation, increase vascular permeability, and trigger plasma extravasation of cells in the region of the nerve termini (see, e.g., Gamse et al.,
Eur. J Pharmacol
., 114, 61-66 (19985); Brain et al.,
Nature
, 313, 54-56 (1985); Reeh et al.,
Brain Res
., 384, 42-50 (1980); Katz et al.,
Am. J. Med
., 101, 1A55S-63S (1996)). Additionally, tachykinins effect degranulization of mast cells, which, in turn, release histamine. Thus, antidromic stimulation of nociceptors mediates the characteristic “wheal and flare” reaction. characterized by tissue swelling through the direct action of released substance P as well as indirectly, such as via increased local histamine concentration from mast cells (Katz, supra; Foreman et al.,
Agents and Actions
, 13, 105-226 (1983)). Within joints, such swelling is associated with arthritis (Levine et al.,
J. Immunol
., 135, 843S-47S (1985); Levine et al.,
Science
, 226, 547-49 (1984)). Additionally, as mentioned, nociceptor termini are arranged in loose networks. Such networks effect cross-talk and interaction between nociceptor termini. Thus, stimulation of nociceptors effects a positive feedback response on the nociceptors themselves, as substance P sensitizes nociceptors, and as histamine stimulates the nociceptors by reducing their threshold (Lembeck et al.,
Trends Neurosci
., 6, 106-08 (1983); Weihe,
Ann. N.Y. Acad. Sci
., 632, 283-95 (1991)).
Aside from mediating local physiological change to noxious stimuli, the nociceptors transmit signals from the periphery to the central nervous system. The neural pathways primarily innervated by nociceptors are associated with pain sensation. In this regard, the organization of their spinal innervation is important for the overall sensation of pain. Signals received by the aforementioned rising spinal neural pathways represent aggregation or summation of signals received from nociceptors from a given level (or segment) of afferent inputs, whether the nociceptive nerve termini lie in the skin or internal organs. This organization of afferent inputs generally produces a segmental map or “dermatome” representation of skin and internal organs relating to segmental innervation, although some longitudinal cross-talk occurs. Due to this aggregation, signals received from internal organs are often “felt” or experienced as if they originated in the same dermatome as the internal organ (giving rise to phenomena such as “phantom pain” or “referred pain”). A similar arrangement exists for cranial nerves. Thus, there are relatively consistent dermatomal representations of internal organs on the human body surface.
The neuroactive peptides (notably substance P) released by nociceptors at the sites of their synapses in the central nervous system can simultaneously stimulate other innervating nociceptive efferent termini within the central nervous system. Due to antidromal signal conductance along such nociceptors from the central nervous system, the peripheral termini of nociceptors in areas distant from the situs of the noxious stimuli can be caused to release tachykinins and other peptides. Thus, lateral cross-talk or reflexive input in the spinal column can lead to a nociceptor mediated “neurogenic inflammation” in an area separate from the initial noxious stimulus (e.g., skin on the contralateral side, joints, internal organs, etc.) within the same dermatome (Levine et al.,
J. Neurosci
., 5, 1380-85 (1985)). Similarly, nociceptive input from termini lying in a given area of skin can often be “felt” or experienced in a similar locus on the contralateral side of the animal, particularly within the same dermatome.
Considering their dual role in sensing pain and in effecting local responses to nociceptive stimuli, several efforts have focused on blocking or attenuating nociceptor activity. One method of attenuating nociceptor activity is via capsaicin, the active agent of red peppers. Capsaicin acts on C-fibers to deplete them of neuropeptides (Janscóet al.,
Naunyn
-
Schmiedberg Arch. Pharmacol
., 313, 91-94 (1980)), leading to diminished response to noxious stimuli. Capsaicin can be applied topically, such as in a cream, to the skin, and it will diffuse through the skin to act on the subcutaneous C-fibers. Using capsaicin to block C-fiber response poses several drawbacks. Notably, the compound can cause degeneration of the C-fibers (Janscóet al.,
Br. J. Pharmacol
., 31, 138-51 (1967); Anton et al.,
Neurosci. Lett. Supp
., 22, 31 (1985)). Moreover, capsaicin can irreversibly decrease the amount of substance P in the skin (Gamse et al.,
Br. J. Pharmacol
., 68, 207-13 (1980); Reeh et al., supra.). Some reports note that the compound must be applied repeatedly to be effective (Zochodne, et al.,
J. Can. Sci. Neurol
., 20, 69-72 (1993)). Also. many formulations for topical capsaicin application are incompatible with broken (e.g., wounded) skin. Furthermore, due to its mode of action by depleting the neuropeptides associated with pain, capsaicin application initially leads to acutely heightened pain sensation and inflammation. This acute pain is experienced as an intolerable burning in some patients and renders controlled or blind studies involving capsaicin difficult or impossible (Kost et al.,
New Eng. J. Med
., 335, 32-42 (1996)).
Another means of affecting the nociceptors is with gold salts. For example, gold salts are effective against progressive joint destruction in patients with arthritis (Gottleib, 796-814 in
Textbook of Rheumatology
, Kelly et al., eds. (W. B. Saunders, Philadelphia (1981)). Gold salts reduce swelling and pain through an irreversible neurotoxicity specific for nociceptors (Levine et al.,
Arthritis Rheumat
., 29, 897-901

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