Differential roles of neurokinin 1 and neurokinin 2 receptors in the development and maintenance of heat hyperalgesia induced by acute inflammation

Following induction of acute inflammation by intraarticular injection of kaolin and carrageenan into the knee joint in rats, there was a significant decrease in the withdrawal latency to radiant heat applied to the paw (i.e. heat hyperalgesia), an increased joint circumference and increased joint temperature. A neurokinin 1 (NK 1 ) receptor antagonist (CP‐99,994, 10 m m ) had no effect on the paw withdrawal latency when it was administered spinally through a microdialysis fibre before the induction of inflammation. Pretreatment with a NK 2 receptor antagonist (SR48968, 1 m m ) administered spinally through the microdialysis fibre prevented the heat hyperalgesia from developing in the early stages of the inflammation. Post‐treatment through the microdialysis fibre with the NK 1 receptor antagonist (0.0110 m m ) was effective in reversing the heat hyperalgesia. In contrast, post‐treatment spinally with the NK 2 receptor antagonist (0.011 m m ) had no effect on the heat hyperalgesia. The inactive stereoisomers of the NK 1 receptor antagonist, CP100,263, or the NK 2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. Pretreatment systemically with the NK 1 receptor antagonist (30 mg kg −1 ) had no effect on the heat hyperalgesia or pain‐related behaviour ratings where 0 is none and 5 is non weight bearing and complete avoidance of limb contact. Pretreatment with a NK 2 receptor antagonist (10 mg kg −1 ) systemically prevented the heat hyperalgesia and pain‐related behaviour ratings from developing in the early stages of the inflammation. The inactive stereoisomers of NK 1 receptor antagonist, CP100,263, or the NK 2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. Post‐treatment systemically with either the NK 1 (0.130 mg kg −1 ) or the NK 2 (0.110 mg kg −1 ) receptor antagonist resulted in a dose‐dependent reversal of the heat hyperalgesia. Pain‐related behaviour ratings were reduced by post‐treatment only with the NK 1 receptor antagonist. The inactive stereoisomers of the NK 1 receptor antagonist, CP100,263, or the NK 2 receptor antagonist, SR48965, administered at the same doses, had no effect on the behavioural responses. Direct pretreatment of the knee joint with either the NK 1 (30 mg) or the NK 2 (10 mg) receptor antagonist prevented the heat hyperalgesia from developing without affecting joint swelling. The inactive stereoisomers of the NK 1 receptor antagonist, CP100,263, or the NK 2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. There appears to be a differential role for the spinal tachykinin receptors in the development and maintenance of the heat hyperalgesia associated with acute joint inflammation. The NK 2 receptors appear to be activated early in the development of the heat hyperalgesia and NK 1 receptors are involved in the maintenance of the heat hyperalgesia. Peripherally, both NK 1 and NK 2 receptors are involved in the development of heat hyperalgesia and pain‐related behaviour ratings induced by acute inflammation.British Journal of Pharmacology (1997) 120 , 1263–1273; doi: 10.1038/sj.bjp.0701044