PHARMACODYNAMICS AND DRUG ACTION Pain and hvperalgesia after intradermal injection oi'bradfknin in humans Pain and hyperalgesia, the perceptual companions of tissue injury and inflammation, are thought to be in part attributable to the sensitization of primary afferent nociceptors by endogenously released chemi- cals, such as bradykinin. Bradykinin (0.1 to 10 nmol in 10 PI) evoked a dose-dependent pain, hyperal- gesia to heat stimuli, and wheal and flare when injected in a double-blind manner into the volar forearm intradermally. Though hyperalgesia to mechanical stimuli is a conspicuous feature of inflammatory pain, none was measurable for any of the bradykinin doses in response to graded nylon monofilament probes. A second injection of bradykinin (5- or 30-minute intervals) at the same site produced markedly less pain and hyperalgesia to heat stimuli, indicating that the algesic and hyperalgesic effects of bradykinin undergo tachyphylaxis. These findings suggest that bradykinin alone cannot account for all aspects of the hyperalgesia that occurs after inflammation. (CLIN PWCOL THER 1991;50:721-9.) Donald C. Manning, MD, PhD, Srinivasa N. Raja, MD, Richard A. Meyer, MS, and James N. Campbell, MD Baltimore, Md. Tissue injury and inflammation lead to an enhanced state of pain sensitivity termed hyperalgesia. Hyperal- gesia is characterized by a decrease in pain threshold, by an increase in pain in response to suprathreshold stimuli and, occasionally, by pain in the absence of external stimuli (i.e., spontaneous pain). ' 92 The neural mechanisms of hyperalgesia are believed to involve, at least in part, the sensitization of the primary affer- ent nociceptive fiber^.^ Nociceptor sensitization is be- lieved to be chemically mediated, but the role of the specific chemical mediators of inflammation is un- clear. To understand better the sensory actions of inflam- From the Departments of Anesthesiology and Critical Care Medi- cine, Neurosurgery and the Applied Physics Laboratory, Johns Hopkins University. Supported by Nova Pharmaceutical Company, Baltimore, Md. (Dr. Manning) and by grants NS-26363 and NS-14447 from the Na- tional Institutes of Health, Bethesda, Md. Received for publication May 3 1, 1991; accepted Aug. 20, 1991. Reprint requests: Donald C. Manning, MD, PhD, Department of AnesthesiologyICritical Care Medicine, Blalock 14, Johns Hop- kins Hospital, 600 North Wolfe St., Baltimore, MD 21205. 1311/33260 matory mediators, we have chosen to study their ef- fects individually, starting with bradykinin. A compel- ling case can be made that the nine amino acid peptide bradykinin and related kinins are involved in nocicep- tion. Autoradiographic studies have revealed that high-affinity binding sites for bradykinin are selec- tively localized to areas involved in nociception, for example, the substantia gelatinosa of the spinal cord, the dorsal root ganglia, and dorsal roots.4 Bradykinin is produced in injured tissue and is known to be alge- sic when given e x ~ ~ e n o u s l ~ . ~ ~ ~ Bradykinin produces pain when administered to human subjects by different routes, including intradermal, intravenous, intraperito- neal, and blister b a ~ e . ~ . ' ~ These early studies were not quantitative and were designed to study acute pain, not hyperalgesia. Recently, a quantitative study of in- tradermal bradykinin administration in humans re- ported pain and cutaneous wheal and flare, but only a single dose was used and cutaneous hyperalgesia was not evaluated.12 To characterize adequately brady- kinin's actions within the skin, we chose to study both the evoked pain and the alteration in heat and mechan- ical sensibility (hyperalgesia) after the injection of bradykinin.