Pain
-
Although much attention has been focused in recent years on nitric oxide synthase (NOS) as an enzyme intimately involved in many types of nociceptive signaling, the enzyme heme oxygenase (HO) has received little attention. Yet, HO produces gaseous second messenger molecule CO which, like NO, has proven to be an important neurotransmitter in the CNS. In these studies we provide detailed evidence that HO activity is critical to formalin-induced licking behavior in mice. ⋯ Mice with a targeted disruption of the HO-2 gene were found to have greatly reduced licking times. Furthermore, Sn-P did not further reduce licking times when administered to HO-2 knockout animals. Taken together our evidence indicates that HO plays an important role in nociceptive signaling related to inflammatory-type pain, and that HO-2 is the isozyme mediating this nociception.
-
This study examined the release of several amino acids after induction of knee joint inflammation in rats using kaolin and carrageenan. During the initial 10-min collection after knee joint injection with the irritants, the concentration of glutamate and the nitric oxide metabolites, arginine and citrulline, doubled. ⋯ Direct knee joint administration of lidocaine prevented the increases in amino acid concentration measurable by microdialysis probe inserted into the joint. These data suggest the possibility that glutamate may be released by neuronal endings in the joint.
-
Comparative Study
Effects of midazolam in the spinal nerve ligation model of neuropathic pain in rats.
Potential changes in the spinal GABAergic activity after nerve injury were studied by comparing the effects of systemic administration of the benzodiazepine midazolam on the noxious evoked responses of dorsal horn in rats with spinal nerve ligation of neuropathy and control animals. The tight ligation of the L(5) and L6 spinal nerves was performed in adult male Sprague-Dawley rats and resulting mechanical and cold allodynia were assessed with von Frey hairs and the acetone drop test. Single unit extracellular recordings of dorsal horn neurones were performed 15-18 days after the surgery under halothane anaesthesia using transcutaneous electrical stimulation of the receptive field at three times the C-fibre threshold. ⋯ The inhibitory effects of s.c. midazolam were significantly reversed by i.t. administration of flumazenil, suggesting a spinal site of action. Midazolam reduced C-fibre evoked firing significantly more in the spinal nerve ligation model than in the non-operated or sham controls. These results indicate changes in the spinal GABAergic system in the neuropathic animals and could be of importance in the development of new treatments for neuropathic pain.
-
We examined the relation between ectopic afferent firing and tactile allodynia in the Chung model of neuropathic pain. Transection of the L5 spinal nerve in rats triggered a sharp, four- to six-fold increase in the spontaneous ectopic discharge recorded in vivo in sensory axons in the ipsilateral L5 dorsal root (DR). The increase, which was not yet apparent 16 h postoperatively, was complete by 24 h. ⋯ Axotomy triggers a wide variety of changes in the neurochemistry and physiology of primary afferent neurons. Investigators studying DRG neurons in culture need to be alert to the rapidity with which axotomy, an inevitable consequence of DRG excision and dissociation, alters key properties of these neurons. Our identification of a specific population of neurons whose firing properties change suddenly and synchronously following axotomy, and whose activity is associated with tactile allodynia, provides a powerful vehicle for defining the specific cascade of cellular and molecular events that underlie neuropathic pain.
-
An injury to a peripheral nerve in animals often leads to signs of neuropathic pain including hyperalgesia to heat, cold and mechanical stimuli. The role of injured and intact nerve fibers in mechanical hyperalgesia was evaluated in rats subjected to an L5 spinal nerve ligation-and-cut ('modified SNL lesion'). To assess the contribution of injured afferents, an L5 dorsal rhizotomy was performed immediately before, or 7 days after the modified SNL lesion. ⋯ These results suggest that, after L5 spinal nerve ligation-and-cut, mechanical hyperalgesia develops and persists independent of input from injured afferents. We propose that the Wallerian degeneration that develops after a nerve injury leads to interactions between the degenerating fibers of the injured spinal nerve and the intact fibers of adjacent spinal nerves. This leads to changes in the intact fibers that play a critical role for both initiation and maintenance of mechanical hyperalgesia.