The present invention relates generally to methods and compositions for the treatment of pain. More specifically, the present invention relates to novel chimeric peptides for the treatment of pain.
Two million people in the United States suffer from chronic pain. Pain is caused by a highly complex perception of an aversive or unpleasant sensation. The sensation of pain begins with noxious stimulation of free nerve endings, which leads to activation of different types of nociceptive afferent fibers. These fibers include Axcex4 fibers and C fibers. Axcex4 fibers are small diameter, thinly myelinated fibers that transmit sharp, prickling pain. C fibers are unmyelinated and conduct more slowly and transmit dull, aching pain. Repeated stimulation of pain fibers can lead to hyperalgesia, or a lowering of the threshold for activation of nociceptors.
Primary afferent fibers Axcex4 or C from the damaged periphery synapse release a variety of chemical mediators. These mediators include glutamate and substance P (xe2x80x9cSPxe2x80x9d), a nociceptive peptide. SP has long been recognized and identified as a neurotransmitter intimately associated with the transfer of painful or nociceptive stimuli from peripheral receptive fields into the CNS. This neuropeptide is involved in pain signaling and the maintenance of the chronic pain state. SP is the prototypic member of a family of related peptides named tachykinins, all of which were initially characterized by contractile activity on isolated smooth muscle preparations. SP is also found in the brain, spinal cord, spinal ganglia, and intestine of all vertebrates, including man.
SP is present in small-diameter sensory fibers that mediate nociceptive inputs in the spinal cord, and it specifically excites nociceptive neurons in this region. SP is released in the spinal cord in vivo, upon activation of nociceptive primary sensory fibers. Direct application of microgram doses of SP into the lumbar spinal subarachnoid produces hyperalgesia, i.e., an increased sensitivity to pain. The release of SP can be blocked by administration of morphine and opioid peptides in vivo and in vitro. For example, intrathecal administration of morphine blocks the hyperalgesic effects of exogenously administered SP. See, Hyden and Wilcox, Eur. J. Pharmacol., 86: 95-98 (1983); and J. Pharmacol. Exp. Ther. 226: 398-404 (1983).
While opioids can be effective for the treatment of chronic pain, they frequently have side effects, including respiratory depression, urinary retention, nausea and vomiting, pruritis, and sedation. Moreover, repeated daily administration of opioids eventually produces tolerance, whereby the dose of the drug must be increased in order to maintain adequate analgesia, and may also initiate physical dependence. If tolerance develops and the level of opioids is insufficient, withdrawal symptoms such as diarrhea, sweating, tremors, anxiety, and fever may result. These concerns have prompted a search for new analgesics with limited side effects and that show decreased susceptibility to tolerance.
The present invention provides a novel chimeric peptide having an opioid moiety that binds to an opioid receptor and a nociceptive moiety that binds to a nociceptive receptor, such as NK1. The opioid moiety may be directed to any of the opioid receptor types, including the xcexc, xcex4, or xcexa receptor
For example, the chimeric peptide can include an xcexc-receptor binding opioid moiety and an NK1-binding SP moiety. In one embodiment this chimeric peptide has the sequence: Tyr-Pro-Phe-Phe-Gly-Leu-Met-NH2 (SEQ ID NO:42).
The chimeric peptides may be designed to have a plurality of SP moieties and a plurality of opioid moieties. The plurality of opioid moieties may be directed to the same receptor type, or, alternatively, the plurality of opioid moieties may be directed to different opioid receptor types.
The invention provides pharmaceutical compositions including chimeric peptides and a pharmaceutically acceptable carrier useful for the treatment of pain.
The invention also provides a method of treating pain by administering the chimeric peptide capable of binding to both an opioid receptor and the NK1 receptor admixed with a pharmaceutically acceptable carrier, such as pharmaceutical sterile saline. The peptide may be administered intrathecally (IT), intracerebrovertricularlly (ICV) or systemically, for example, intraperitoneally (IP). Solubility of the chimeric peptides may be enhanced by admixture with a solubilizing agent, for example, cyclodextran. In a alternative embodiment, a chimeric peptide is administered in conjunction with one or more non-chimeric opioid drugs.
Among the advantages of the invention is that the chimeric peptides produce effective analgesia yet inhibit the development of tolerance.
The details of one or more embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless expressly stated otherwise, the techniques employed or contemplated herein are standard methodologies well known to one of ordinary skill in the art. The examples of embodiments are for illustration purposes only. All patents and publications cited in this specification are incorporated herein by reference.