Peripheral nerve injury produces signs of neuropathic pain including tactile allodynia and thermal hyperalgesia, sensory modalities which may be associated with different neuronal pathways. Studies of spinally-transected, nerve-injured rats have led to suggestions that thermal hyperalgesia may be mediated predominately through local spinal circuitry whereas ascending input to supraspinal sites is critical to the manifestation of tactile allodynia. Here, the nature of ascending spinal input mediating tactile allodynia was explored using selective spinal lesions. Male Sprague-Dawley rats received L(5)/L(6) spinal nerve ligation (SNL) and ipsilateral or contralateral (relative to the SNL side) lesions including spinal hemisections and bilateral and unilateral dorsal column lesions. The rats were maintained in a sling and monitored for tactile allodynia by measuring withdrawal thresholds to probing with von Frey filaments 24 h after the hemisection. Rats receiving dorsal column lesions demonstrated no motor deficits while rats receiving spinal hemisection showed paralysis of the paw which nevertheless responded to strong noxious stimulation. Spinal hemisection ipsilateral, but not contralateral, to SNL completely abolished tactile allodynia while maintaining spinal nocifensive reflexes to noxious pinch. Bilateral and ipsilateral dorsal column lesions blocked tactile allodynia while contralateral dorsal column lesions did not. Administration of lidocaine into the nucleus gracilis ipsilateral to SNL also blocked tactile allodynia, but did not alter thermal hyperalgesia in SNL rats or increase thermal nociceptive responses in sham-operated rats. Lidocaine microinjected into the contralateral nucleus gracilis produced no changes in responses to tactile or thermal stimuli in either group. These results indicate that tactile allodynia after peripheral nerve injury is dependent upon inputs to supraspinal sites. Furthermore, it is apparent that afferent signals interpreted as tactile allodynia course through the ipsilateral dorsal columns and are relayed through the nucleus gracilis. This neuronal pathway is consistent with the interpretation that tactile allodynia pursuant to peripheral nerve injury is transmitted to the central nervous system by means of large diameter, myelinated fibers.

We have previously shown that the naturally occurring levomorphine at a subanalgesic picomolar dose pretreated i.t. induces antianalgesia against levo-morphine-produced antinociception. We now report that the synthetic stereo-enantiomer dextro-morphine, even at an extremely low femtomolar dose, induces antianalgesia against levo-morphine-produced antinociception using the tail-flick (TF) test in male CD-1 mice. Intrathecal pretreatment with dextro-morphine (33 fmol) timedependently attenuated the i.t. levo-morphine-produced TF inhibition for 4 h and returned to the preinjection control level at 24 h. Intrathecal pretreatment with dextro-morphine (0.3-33 fmol), which injected alone did not affect the baseline TF latency, dose-dependently attenuated the TF inhibition produced by i.t.-administered levo-morphine (3.0 nmol). The ED 50 value for dextro-morphine to induce antianalgesia was estimated to be 1.07 fmol, which is 71,000-fold more potent than the ED 50 value of levo-morphine, indicating the high stereoselective action of dextro-morphine over levo-morphine for the induction of antianalgesia. Like levo-morphine, the dextro-morphineinduced antianalgesia against levo-morphine-produced TF inhibition was dose-dependently blocked by the nonopioid dextro-naloxone and its stereo-enantiomer levo-naloxone, a nonselective -opioid receptor antagonist. The antianalgesia induced by levo-morphine and dextro-morphine is reversed by the pretreatment with the glial inhibitor propentofylline (3.3-65 nmol), indicating that the antianalgesia is mediated by glial stimulation. The findings strongly indicate that the antianalgesia induced by levo-morphine and dextro-morphine is mediated by the stimulation of a novel nonopioid receptor on glial cells.Naturally occurring levo-morphine, which is isolated from the juice of the opium poppy, Papaver somniferum, is stereochemically identified as a levorotatory isoform of morphine. levo-Morphine produces potent analgesic and other major pharmacological effects, which are mainly mediated by the stimulation of -opioid receptors. The synthetic dextro-enantiomer of levo-morphine has minimal activity in the -opioid receptor binding assay, the electrically stimulated guinea pig ileum assay, and the inhibition of adenylate cyclase activity in the neuroblastoma ϫ glioma hybrid cell homogenates, indicating that it does not interact with -opioid receptors (Jacquet et al., 1977). Unlike levo-morphine, which produces potent levo-naloxone reversible analgesia, dextro-morphine microinjected into the periaqueductal gray in rats produces minimal analgesia (Jacquet et al., 1977). In the present study, i.t. pretreatment with dextro-morphine, which injected alone does not affect baseline nociceptive latency, attenuates the antinociception produced by i.t.-administered levo-morphine. The phenomenon of the attenuation of levo-morphineproduced analgesia by dextro-morphine has been defined as antianalgesia (Wu et al., 2004b).Nonselective -opioid receptor antagonist levo-naloxone and nonopioid receptor ant...

Intrathecal (i.t.) pretreatment with a low dose (0.3 nmol) of morphine causes an attenuation of i.t. morphine-produced analgesia; the phenomenon has been defined as morphine-induced antianalgesia. The opioid-produced analgesia was measured with the tail-flick (TF) test in male CD-1 mice. Intrathecal pretreatment with low dose (0.3 nmol) of morphine time dependently attenuated i.t. morphine-produced (3.0 nmol) TF inhibition and reached a maximal effect at 45 min. Intrathecal pretreatment with morphine (0.009 -0.3 nmol) for 45 min also dose dependently attenuated morphine-produced TF inhibition. We have previously reported that intrathecal (i.t.) pretreatment with an endogenous -opioid peptide, endomorphin-2 (0.05-1.75 nmol), attenuates the antinociception produced by opioid agonists. The antianalgesic effect is caused by the release of dynorphin A(1-17) through the stimulation of a subtype of -opioid receptors. The unique features of this endomorphin-2-induced antianalgesic action are that there is a lag period before dynorphin A(1-17) is released, and the antianalgesic action of endomorphin-2 corresponds with the time course of dynorphin release Wu et al., 2003). Furthermore, i.t. administered endomorphin-2 at larger doses (5.25-35 nmol) produces analgesia by itself through activation of spinal -opioid receptors (Ohsawa et al., 2001), whereas its delayed antianalgesic action is manifested more easily at small doses of endomorphin-2 by its ability to attenuate the analgesic action of other opioids administered after endomorphin-2 pretreatment.There are indications from the literature that morphine may have an antianalgesic action. Pretreatment with a low dose of naloxone (0.00028 fmol) or dynorphin A antiserum given i.t. enhances the analgesic effect of intracerebroventricularly and i.t.-administered morphine (Fujimoto and Rady, 1989;Holmes and Fujimoto, 1993). Studies performed by Crain and Shen (1990, 2000 indicate that even though generally morphine has a depressant effect on action potential duration in mouse dorsal root ganglion preparations, very low doses (1 fmol-1 pmol) of morphine produce the opposite effect by prolonging the duration of the action potential, an excitatory action. Recent studies also have shown that morphine and opioid compounds not only simply elicit