The resolution of neuropathic hyperalgesia following motor and sensory functional recovery in sciatic axonotmetic mononeuropathies.
Nerve lesions producing extensive axonal loss can induce painful hyperalgesic states in man. The affect of axonal regeneration and end-organ reinnervation on hyperalgesia and pain is controversial. This study used two axonotmetic models, the sciatic crush injury (CI) and the sciatic chronic constrictive injury (CCI), to investigate the affects of nerve regeneration and reinnervation on hyperalgesia and presumed painful behavior in rats. The sciatic CI resulted in a transient loss of both sciatic motor function and the withdrawal response to pinch and heat in the sciatic distribution. Extensive recovery of motor function, pinch and heat response occurred over days 23-38 post-crush injury. This temporally corresponded with a plateau in the hindpaw autotomy score and a resolution of the saphenous-mediated pressure and heat hyperalgesia (adjacent neuropathic hyperalgesia; ANH) which developed over the medial dorsum of the hindpaw following the sciatic CI. In contrast, with sciatic transection and distal stump excision, no motor recovery occurs, large areas of the hindpaw remain unresponsive to heat and pinch, and the saphenous mediated ANH fails to resolve over a period of 3 months. When sciatic CI was compared to contralateral sciatic transection within the same rat, the bilateral saphenous-mediated pressure and heat thresholds were initially identical, but by 23-27 days post-crush, the crush side thresholds became hypoalgesic relative to the section side. This demonstrates an attenuation of the crush-induced ANH which temporally corresponds to the recovery of motor and sensory function. When the sciatic nerve was proximally crushed and distally transected (3 cm below the crush site), the saphenous-mediated pressure and heat threshold changes were identical (over 6 weeks of serial testing) to those produced by a contralateral sciatic transection within the same rat. This indicates that the microenvironments surrounding the regenerating axon tips did not differentially affect the development of ANH following sciatic CI or transection. The sciatic CCI resulted in a transient loss of hindpaw motor function without the loss of pinch or heat withdrawal responses in the sciatic distribution. Motor function recovery occurred primarily over days 23-59 post-ligature. During this prolonged period of motor function recovery there was a resolution of the sciatic-mediated plantar surface heat hyperalgesia and the saphenous-mediated heat ANH. The above data support the hypothesis that the successful regeneration of distal axons after axonotmetic lesions can initiate the resolution of neuropathic hyperalgesia.
Kingery
Wade S
WS
Physical Medicine and Rehabilitation Service, Veterans Affairs Medical Center, Palo Alto, CAUSA Department of Functional Restoration, Stanford Medical School, Stanford, CAUSA.
Lu
John D
JD
Roffers
John A
JA
Kell
David R
DR
D000818:Animals; D001369:Axons / Q000502:physiology*; D006614:Hindlimb / Q000502:physiology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology*; D008297:Male; D009046:Motor Neurons / Q000502:physiology*; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology; D017288:Pain Threshold / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries / Q000503:physiopathology*; D012652:Self Mutilation / Q000503:physiopathology / Q000523:psychology