The Mechanical Antihyperalgesic Effect of Intrathecally Administered MPV-2426, a Novel α2-Adrenoceptor Agonist, in a Rat Model of Postoperative Pain

The method commonly used for catheterization of the lumbar subarachnoid space in the rat implies inserting the catheter through the atlanto-occipital (A-O) membrane and moving the catheter caudally along the spinal cord. The method is associated with a considerable morbidity. A method for direct catheterization of the lumbar subarachnoid space was therefore developed. Major surgery was avoided by using a catheter-through-needle technique. Of 32 rats, none died. There were no signs of neurological disturbances, and all animals gained weight as normal the first week after implantation. Data from rats catheterized by the A-O method were used for comparison. Of 40 animals, 2 died, 11 showed signs of neurological disturbances, and the mean weight was reduced during the first week after catheterization. The two groups of animals showed different behavioural responses to intrathecal injection of N-methyl-D-aspartate (NMDA, 0.1-1.6 mM, 15 microliters) which is thought to stimulate afferent pathways mediating nociception. Animals with a lumbar catheter showed licking, biting and scratching behaviour in a dose-related manner for concentrations up to 1.6 mM. The animals with A-O catheters showed a maximum level of this behaviour already at 0.4 mM, while 0.5 mM induced convulsions. A possible explanation of this difference in response to NMDA could be a long-lasting pain state in the A-O group, caused by catheter-induced changes in the spinal cord and by the extensive surgery. It is concluded that the direct lumbar catheterization has several advantages compared to the A-O method, decreasing the suffering of the animals, the neurological disturbances and the interference with nociceptive functions of the spinal cord.

The mechanisms by which peripheral nerve injuries sometimes lead to causalgia, aberrant burning pain peripheral to the site of nerve damage, are uncertain, although the sympathetic nervous system is known to be involved. Whether such syndromes could be the result of the development of responsiveness by some cutaneous pain receptors (C-fiber nociceptors) to sympathetic efferent activity as a consequence of the nerve injury was tested in an animal model. After nerve damage but not in its absence, sympathetic stimulation and norepinephrine were excitatory for a subset of skin C-fiber nociceptors and enhanced the responsiveness of these nociceptors to tissue-damaging stimulation. These effects were demonstratable within days after nerve lesions, occurred at the cutaneous receptive terminal region, were manifest in sensory fibers that had not degenerated after the injury, and were mediated by alpha 2-adrenergic-like receptors.

Evidence indicates that excitatory amino acids (EAAs) like glutamate and aspartate are important in the processing of nociceptive information in the dorsal horn of the spinal cord. Recently, the role of particular EAA receptors in pain transmission and facilitated pain states has been examined utilizing spinal administration of specific receptor antagonists. Most investigators have studied the involvement of N-methyl-D-aspartate (NMDA) EAA receptors in hyperalgesia and nociception; less is known about the importance of non-NMDA EAA receptors in animal models of persistent pain. To study the role of spinal non-NMDA EAA receptors in pain behaviors caused by an incision, we examined the effect of i.t. administered non-NMDA EAA receptor antagonists in a rat model of postoperative pain. Rats with i.t. catheters were anesthetized and underwent a plantar incision. Withdrawal threshold to punctate stimulation applied adjacent to the wound using von Frey filaments, response frequency to application of a non-punctate stimulus applied directly to the wound and non-evoked pain behaviors were measured before and after administration of i.t. 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX), or vehicle. A separate group of animals were also tested for motor impairment caused by these drugs. In the vehicle-treated group, the median withdrawal threshold for punctate hyperalgesia decreased from 522 mN before surgery to 39 mN 2 h later; hyperalgesia was persistent. Intrathecal administration of 5 or 10 nmol of NBQX returned the withdrawal threshold toward preincision values; the median withdrawal thresholds were 158 and 360 mN, respectively. Intrathecal administration of 10 nmol of DNQX similarly increased the withdrawal threshold after incision. In separate groups of animals, i.t. administration of 5 or 10 nmol of NBQX decreased the response frequency to a non-punctate stimulus applied directly to the incision from 100+/-0% 2 h after surgery to 22+/-11 and 0+/-0% 30 min after drug injection, respectively. Similar results were observed with i.t. administration of 10 nmol of DNQX. Intrathecal NBQX also inhibited non-evoked pain behavior. In conclusion, non-NMDA receptor antagonists produced a marked decrease in pain behaviors in this model of postoperative pain. Thus, non-NMDA receptors are important for the maintenance of short-term pain behaviors caused by an incision and drugs blocking these receptors may be useful for the treatment of postoperative pain in patients.