Neuropathic pain: Early spontaneous afferent activity is the trigger

Abstract

Intractable neuropathic pain often results from nerve injury. One immediate event in damaged nerve is a sustained increase in spontaneous afferent activity, which has a well-established role in ongoing pain. Using two rat models of neuropathic pain, the CCI and SNI models, we show that local, temporary nerve blockade of this afferent activity permanently inhibits the subsequent development of both thermal hyperalgesia and mechanical allodynia. Timing is critical-the nerve blockade must last at least 3-5 days and is effective if started immediately after nerve injury, but not if started at 10 days after injury when neuropathic pain is already established. Effective nerve blockade also prevents subsequent development of spontaneous afferent activity measured electrophysiologically. Similar results were obtained in both pain models, and with two blockade methods (200 mg of a depot form bupivacaine at the injury site, or perfusion of the injured nerve just proximal to the injury site with TTX). These results indicate that early spontaneous afferent fiber activity is the key trigger for the development of pain behaviors, and suggest that spontaneous activity may be required for many of the later changes in the sensory neurons, spinal cord, and brain observed in neuropathic pain models. Many pre-clinical and clinical studies of pre-emptive analgesia have used much shorter duration of blockade, or have not started immediately after the injury. Our results suggest that effective preemptive analgesia can be achieved only when nerve block is administered early after injury and lasts several days.

Rapid Synaptic Remodeling in the Adult Somatosensory Cortex following Peripheral Nerve Injury and Its Association with Neuropathic Pain

“…3C), our data suggest that new cortical connections are rapidly generated after neuro-pathic injury with simultaneous, but relatively slow, elimination of preexisting circuits, followed by refinement of the new connections. Because early afferent hyperactivity is the key driver for development of CNS changes and allodynia (Devor, 2006), we conducted local blockade of the injured nerve throughout the early phase, which prevents afferent ectopic firing even after its action is finished (Xie et al, 2005), by directly implanting an Elvax-TTX immediately after PSL. Such temporary blockade prevented the increase of spine gain and loss in the S1 ( p Ͼ 0.3) (Fig.…”

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

“…immediately/first few days following induction of peripheral neuropathy) of nerve injury (Araujo et al, 2003;Gonzalez-Darder et al, 1986;Lindia et al, 2005;Seltzer et al, 1991a;Sotgiu et al, 1994;Sotgiu et al, 1995b;Xie et al, 2005Xie et al, , 2007Yamamoto et al, 1993), but see Suter et al (2003). Xie et al (2005) reported that blocking peripheral nerve input during the first five days after model induction permanently prevents development of pain-like behavior. Despite important short-term effects of nerve injury, in the light of our present results peripheral drive (≥2 weeks after induction of neuropathy) must nonetheless be seen as being important in the later maintenance phase of other models of peripheral neuropathy.…”

“…One hypothesis suggests that central sensitization at the level of the spinal dorsal horn is maintained independently of primary afferent input (Sandkuhler and Liu, 1998) since input from the periphery is reportedly insufficient to maintain spinal modifications in sensory processing and ultimately neuropathic pain (Burgess et al, 2002;Sun et al, 2005;Xie et al, 2005). Another view suggests that mechanisms at the spinal dorsal horn level require continuous facilitatory input from supraspinal structures Carlson et al, 2007;Gardell et al, 2003;Kauppila et al,1998;Kovelowski et al, 2000;Ossipov et al, 2000;Pertovaara et al, 1997Pertovaara et al, , 2001Porreca et al, 2001;Saade et al, 2006aSaade et al, ,b, 2007Suzuki et al, 2002Suzuki et al, , 2004aVeraPortocarrero et al, 2006).…”

Neuropathic Pain Management in Chronic Laminitis

“…[143][144][145] Experimental evidence and clinical experiences in human medicine indicate that central hyperalgesia can be obliterated by no other treatment modality as effectively as by loco-regional anesthesia and analgesia aimed at interrupting or diminishing impulse trafficking from the site of tissue injury to the CNS and within the dorsal horn of the spinal cord. 56,59,78,[143][144][145][146][147] Those techniques may include wound infiltration or joint injections with local anesthetics, topical local anesthetic application using lidocaine patches, repetitive or even better continuous peripheral nerve blocks, and epidural or intrathecal anesthesia and analgesia.…”