Alan Cowan - US grants

No Abstract Provided

Historically, analgesic pharmacologists have studied animal models of acute pain but have been reluctant or unable to develop and evaluate analgesics in models of chronic pain. The rat paw-formalin procedure represents one of the few pain tests that gives steady (tonic) pain associated with minor tissue damage i.e. pain that may be neurochemically and neurophysiologically different from brief (phasic) pain associated with conventional hot plate and tail flick tests. The overall aim of the proposal is to characterize, under rigorously standardized conditions, important opioids (e.g. buprenorphine, sufentanil), peptides (e.g. neurotensin, cholecystokinin octapeptide), opioid peptides (e.g. dynorphin A) and critical experimental compounds (e.g. U-50,488H) in the formalin model. Test compounds will be studied in this procedure and compared with activities in an untreated paw pressure test of acute pain. Constipation - the second classical effect of opiates - will be measured for each compound in the rat colonic antitransit test and related to corresponding analgesic activities. Test agents will be compared in both endpoints (analgesia and transit) after intrathecal, intracerebroventricular, subcutaneous and, where appropriate, intraperiaqueductal gray administration. This approach will give valuable information on locus of action. Tolerance development will be assessed since tolerance/crosstolerance experiments have traditionally been helpful in the subclassification of analgesics. Additionally, the challenging contention that tolerance to opiates does not occur under chronic pain conditions, will be investigated.

Historically, analgesic pharmacologists have studied animal models of acute pain but have been reluctant or unable to develop and evaluate analgesics in models of chronic pain. The rat paw-formalin procedure represents one of the few pain tests that gives steady (tonic) pain associated with minor tissue damage i.e. pain that may be neurochemically and neurophysiologically different from brief (phasic) pain associated with conventional hot plate and tail flick tests. The overall aim of the proposal is to characterize, under rigorously standardized conditions, important opioids (e.g. buprenorphine, sufentanil), peptides (e.g. neurotensin, cholecystokinin octapeptide), opioid peptides (e.g. dynorphin A) and critical experimental compounds (e.g. U-50,488H) in the formalin model. Test compounds will be studied in this procedure and compared with activities in an untreated paw pressure test of acute pain. Constipation - the second classical effect of opiates - will be measured for each compound in the rat colonic antitransit test and related to corresponding analgesic activities. Test agents will be compared in both endpoints (analgesia and transit) after intrathecal, intracerebroventricular, subcutaneous and, where appropriate, intraperiaqueductal gray administration. This approach will give valuable information on locus of action. Tolerance development will be assessed since tolerance/crosstolerance experiments have traditionally been helpful in the subclassification of analgesics. Additionally, the challenging contention that tolerance to opiates does not occur under chronic pain conditions, will be investigated.

ABSTRACT NOT PROVIDED

The Integrative Pharmacology Core is very active in supporting direct experimentation and in providing other (theoretical/statistical) support services with colleagues both within Temple. University and externally. Studies with combinations of drugs of abuse represented a major activity of the Core. It continues to provide expertise in in vivo pharmacology and drug interaction studies to faculty, technicians, graduate and medical students at Temple University School of Medicine and externally. Beyond Temple, the comprehensive nature of the testing procedures has attracted collaborative interactions over the past 5 years. The Core offers pharmacological testing services for numerous endpoints in mice and/or rat, including: a neurological screen for overt behavior; tests for motor coordination; automatic monitoring of ambulation and stereotypies; analgesic/tolerance tests for acute, persistent and incisional pain; anti-inflammatory activity; antipruritic activity; body and brain temperature measurement; physical dependence/withdrawal; diuresis; oximetry; and stomach emptying, intestinal and colonic transit. The Core personnel also train and/or assist with various techniques such as icv drug administration, microinjection into specific brain nuclei, and microdialysis in various brain sites. In addition, the Core assists in experimental design and data analysis of various drug combinations. This Core has been well utilized by numerous Temple faculty members as well scientists outside of Temple. The services performed by the Core have enabled many investigators without prior experience in in vivo testing to add another dimension to their work without dramatically increasing their budgets. This factor has resulted in new collaborations, sparking novel approaches to solving age-old problems of tolerance and dependence, and innovative ideas for therapeutics. Over the following 5 years, the Integrative Core will be used to evaluate and characterize novel compounds in standard in vivo screens; to improve/develop existing procedures in tune with advancing technology; to provide training in a variety of techniques; to assist in conducting in vivo studies for laboratories that do not normally do such testing; and to collaborate in new research projects both within and without Temple University.