Neuropathic pain as a process: reversal of chronification in an animal model

Abstract

Peripheral neuropathic pain arises from trauma to sensory nerves. Other types of acute neurotrauma such as stroke and spinal cord injury are treated immediately, largely to prevent secondary damage. To pursue the possibility that neuropathic pain may also be amenable to early treatment, a rat model of neuropathic pain was induced using a 2-mm polyethylene cuff implanted around one sciatic nerve. Within 24 hours, hypersensitivity to von Frey hair stimulation appeared, as indicated by decreased paw withdrawal thresholds. When the cuff was removed 24 hours after implantation, readings returned to pre-implantation levels starting as early as day 18. When the cuff was removed after 4 days, there was a period of initial hypersensitivity, and then an increase toward baseline at two time points near the end of the study; therefore, only a partial recovery toward pre-implantation values occurred. Having established that a temporal reversal can occur, the next step examined possible pharmacological reversal. The tachykinin NK1 receptor antagonist, CP-96,345, produced a minor increase in withdrawal thresholds in animals with the cuff left permanently implanted. To determine the effect of early and repeated administration of CP-96,345, it was given daily on days 1–4. The cuff was removed on day 4. Six days later, readings showed reversal of tactile hypersensitivity. We suggest that persistent neuropathic pain occurs from processes that develop over several hours and days, and that some of these processes may be prevented by early medical intervention. Thus, nerve injury in the context of chronic neuropathic pain should be treated in a similar manner to nerve injury resulting from stroke, spinal cord injury, and other types of neurotrauma. We suggest that effective medical intervention within the first few hours after nerve injury may spare a patient from a chronic debilitating pain that may be refractory to later therapies.

Anxiety- and Depression-Like Behavior and Impaired Neurogenesis Evoked by Peripheral Neuropathy Persist following Resolution of Prolonged Tactile Hypersensitivity

“…The test equipment included a standard plastic box for open-field and novel-object recognition tests and O-maze and Y-maze apparatus from Phenome Technologies. Tests were conducted as we described previously (Coutellier and Usdin, 2011;Coutellier et al, 2011). Time spent in the central 50% of the open field, time spent in the O-maze open arms, and the number of Y-maze spontaneous alternations are presented as a percentage of the total time (5 min in each case) or total number of entries.…”

How to erase memory traces of pain and fear

“…Therapeutic interference within the consolidation process may fully prevent the development of lasting (e.g., neuropathic) pain. For example, when neuropathic pain is induced in rats by placing a cuff around the sciatic nerve, mechanical hyperalgesia develops within 24 h. Removal of the cuff 24 h but not 4 days after implantation allows full recovery of mechanical thresholds within 18 days [21]. Likewise, a single intrathecal injection of GABA apparently reverses neuropathic pain permanently when given 1 week after a chronic constriction injury of the sciatic nerve in rats, but not when given more than 2–3 weeks after the injury [22].…”

Investigation of Neuropathology after Nerve Release in Chronic Constriction Injury of Rat Sciatic Nerve

“…This brief and reversible neurologic deficit was identical to the findings using the acute nerve crush or clip model, with spontaneous full recovery after injury [ 19 , 20 ]. Dableh et al [ 5 ] reported that the tactile hypersensitivity induced by temporary mechanical compression can be spontaneously reversed by removing the implanted perineural cuff of the sciatic nerve. They revealed that removal of the cuff at 24 h after hypersensitivity induction led to full recovery to the baseline threshold, whereas removal of the cuff after 4 days demonstrated only partial alleviation.…”

“…If the external compression forces persist, subsequent muscle weakness and atrophy will gradually develop with time, increasing in severity [ 4 ]. With the increase in local compression forces, ischemia of the surrounding connective tissue and nerves might trigger a subsequent cascade of nerve damage and prolonged neuroinflammation [ 5 , 6 ]. The initial histopathological changes of compressive neuropathy induce a breakdown of the blood–nerve barrier and subperineurial edema [ 7 ].…”