Receptor Subtype Mediating the Adrenergic Sensitivity of Pain Behavior and Ectopic Discharges in Neuropathic Lewis Rats

Abstract

Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. We attempted to identify the subtype of alpha-adrenergic receptor (alpha-AR) that is responsible for the sympathetic (adrenergic) dependency of neuropathic pain in the segmental spinal injury (SSI) model in the Lewis strain of rat. This model was chosen because our previous study showed that pain behaviors in this condition are particularly sensitive to systemic injection of phentolamine (PTL), a general alpha-AR blocker. We examined the effects of specific alpha1- and alpha2-AR blockers on 1) behavioral signs of mechanical allodynia, 2) ectopic discharges recorded in the in vivo condition, and 3) ectopic discharges recorded in an in vitro setup. One week after tight ligation of the L5 and L6 spinal nerves, mechanical thresholds of the paw for foot withdrawals were drastically lowered; we interpreted this change as a sign of mechanical allodynia. Signs of mechanical allodynia were significantly relieved by a systemic injection of PTL (a mixed alpha1- and alpha2-AR antagonist) or terazosin (TRZ, an alpha1-AR antagonist) but not by various alpha2-AR antagonists (idazoxan, rauwolscine, or yohimbine), suggesting that the alpha1-AR is in part the mediator of the signs of mechanical allodynia. Ongoing ectopic discharges were recorded from injured afferents in fascicles of the L5 dorsal root of the neuropathic rat with an in vivo recording setup. Ongoing discharge rate was significantly reduced after intraperitoneal injection of PTL or TRZ but not by idazoxan. In addition, by using an in vitro recording setup, spontaneous activity was recorded from teased dorsal root fibers in a segment in which the spinal nerve was previously ligated. Application of epinephrine to the perfusion bath enhanced ongoing discharges. This evoked activity was blocked by pretreatment with TRZ but not with idazoxan. This study demonstrated that both behavioral signs of mechanical allodynia and ectopic discharges of injured afferents in the Lewis neuropathic rat are in part mediated by mechanisms involving alpha1-ARs. These results suggest that the sympathetic dependency of neuropathic pain in the Lewis strain of the rat is mediated by the alpha1 subtype of AR.

Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-α after Spinal Nerve Ligation

“…As reported previously (Zhang et al, 1997;Lee et al, 1999;, all L5R DRG fibers were initially silent during baseline recording (Table 1, Fig. 8, left).…”

“…Most SPAϩ fibers in injured DRG were A-␦ and not A-␤ fibers, which contrasts with the results of others (Lee et al, 1999;Liu et al, 1999). Our sampling of active fibers may have been biased to some degree, because our selection method depended on computer-based matches of TNFevoked spikes to templates of electrically identified fibers.…”

Subthreshold Oscillations Induced By Spinal Nerve Injury In Dissociated Muscle And Cutaneous Afferents Of Mouse DRG

“…Interestingly, axotomy increases the proportion of neurons that display subthreshold oscillations at Vr and on depolarization. This injuryinduced increase in membrane oscillations, and the consequent increase in burst firing, correlates well with ectopic discharge patterns seen in vivo Lee et al 1999;Liu et al 2000b;Study and Kral 1996;Zhang et al 1997), supporting the suggestion that the oscillations made a fundamental contribution to neuropathic dysesthesia and pain (Devor and Seltzer 1999). …”

Sympathetic Vasoconstrictor Antagonism and Vasodilatation Relieve Mechanical Allodynia in Rats With Chronic Postischemia Pain

“…This strongly suggests that the α1-receptor contributes to the mechanical allodynia in CPIP. Lee et al 41 found that α 1 -adrenergic antagonists, but not α 2 -adrenergic antagonists, also reduce mechanical allodynia in rats with segmental spinal injury. Phentolamine and α 1 -but not α 2 -adrenergic antagonists also reduce cold allodynia in rats with S1/S2 spinal nerve ligation.…”