tetrodotoxin and Pain--Postoperative

The rostral ventromedial medulla (RVM) is highly involved in pain signal transmissions. Previous studies have shown that thalidomide is anti-nociceptive. Thus, we evaluated the neurobiological mechanisms of thalidomide in the RVM in the regulation of postoperative pain. We used a rat model of postoperative pain to investigate the effects of intra-RVM thalidomide treatments on postoperative pain, and evaluate the role of cannabinoid receptors in the effects of intra-RVM thalidomide treatments on GABAergic neurotransmission in the RVM neurons. We found intra-RVM thalidomide treatments reduced incisional surgery induced mechanical allodynia. This phenomenon was associated with attenuation of the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) and spontaneous IPSCs (sIPSCs) in RVM neurons. Furthermore, applications of WIN 55,212-3 mesylate, a non-selective cannabinoid receptor antagonist reversed the effects of repeated thalidomide treatment on the frequency but not the amplitude of mIPSCs and sIPSCs. Finally, we found that repeated thalidomide treatment robustly enhanced CB2 receptor expression, but slightly reduced CB1 receptor expression, in the RVM. These results suggested that the antinociceptive effects of thalidomide in the RVM likely involve the attenuation of GABA release, which are critically regulated by cannabinoid receptors.

Topics: Analgesics; Animals; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Hyperalgesia; Inhibitory Postsynaptic Potentials; Male; Medulla Oblongata; Neurons; Pain Measurement; Pain Threshold; Pain, Postoperative; Quinoxalines; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Tetrodotoxin; Thalidomide; Valine

Antisense (AS) oligodeoxynucleotides (ODNs) targeting the Nav 1.8 sodium channel have been reported to decrease inflammatory hyperalgesia and L5/L6 spinal nerve ligation-induced mechanical allodynia in rats. The present studies were conducted to further characterize Nav 1.8 AS antinociceptive profile in rats to better understand the role of Nav 1.8 in different pain states. Consistent with earlier reports, chronic intrathecal Nav 1.8 AS, but not mismatch (MM), ODN decreased TTX-resistant sodium current density (by 60.5+/-10.2% relative to MM; p<0.05) in neurons from L4 to L5 dorsal root ganglia and significantly attenuated mechanical allodynia following intraplantar complete Freund's adjuvant. In addition, 10 days following chronic constriction injury of the sciatic nerve, Nav 1.8 AS, but not MM, ODN also attenuated mechanical allodynia (54.3+/-8.2% effect, p<0.05 vs. MM) 2 days after initiation of ODN treatment. The anti-allodynic effects remained for the duration of the AS treatment, and CCI rats returned to an allodynic state 4 days after discontinuing AS. In contrast, Nav 1.8 AS ODN failed to reduce mechanical allodynia in the vincristine chemotherapy-induced neuropathic pain model or a skin-incision model of post-operative pain. Finally, Nav 1.8 AS, but not MM, ODN treatment produced a small but significant attenuation of acute noxious mechanical sensitivity in naïve animals (17.6+/-6.2% effect, p<0.05 vs. MM). These data demonstrate a greater involvement of Nav 1.8 in frank nerve injury and inflammatory pain as compared to acute, post-operative or chemotherapy-induced neuropathic pain states.

Topics: Animals; Behavior, Animal; Drug Evaluation, Preclinical; Freund's Adjuvant; Hyperalgesia; Inflammation; Injections, Spinal; Ion Transport; Ligation; Male; NAV1.8 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Neuralgia; Neurons, Afferent; Oligodeoxyribonucleotides, Antisense; Pain, Postoperative; Patch-Clamp Techniques; Pressure; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Sodium; Sodium Channels; Spinal Nerves; Stress, Mechanical; Tetrodotoxin; Vincristine

To determine the duration of anesthesia, effect on corneal reepithelialization, and systemic toxicity of topical tetrodotoxin (TTX) administered after excimer laser keratectomy.. Two groups of six rabbits each underwent excimer laser keratectomy in the right eye to create a 5-mm-diameter wound, 75 mm in depth. One group then received a 40-microl aliquot of topical 1 mM TTX into the injured eye, whereas the other group received 40 microl of the sodium citrate vehicle as a control. The rabbits were treated with TTX or vehicle again at 6, 12, 18, and 24 h. Corneal sensation was tested at 3, 6, 9, 12, 15, 18, 21, 24, 30, 32, and 40 h. To determine whether TTX inhibited corneal reepithelialization, compared with vehicle-treated control eyes, the healing rate of the epithelial defect was measured.. Administration of TTX every 6 h for 24 h produced nearly complete anesthesia for > or = 30 h. At 32 h, 8 h after the final application of TTX, there was still significant anesthesia of the TTX-treated corneas (p = 0.0325, Wilcoxon test). Normal corneal sensation in all TTX-treated animals returned at 40 h, or 16 h after the final dose. In contrast, vehicle-treated eyes all had normal sensation for nearly the entire duration of the experiment. At 40 h, the TTX-treated eyes had slightly larger defects than vehicle-treated eyes, 7.85+/-1.74 versus 4.54+/-1.31 mm2 (p < 0.025, t test). However, at 49 h and thereafter, both groups were equally healed (p > 0.05, t test). No systemic toxicity was observed in any of the rabbits.. Topical TTX is a long-acting and nontoxic local anesthetic in a rabbit model of excimer laser keratectomy.

Topics: Anesthesia, Local; Anesthetics, Local; Animals; Cell Movement; Cornea; Epithelium, Corneal; Lasers, Excimer; Ophthalmic Solutions; Pain, Postoperative; Photorefractive Keratectomy; Rabbits; Tetrodotoxin; Wound Healing

The delayed onset of painful paresthesias following trauma to a peripheral nerve is a well recognized but poorly understood phenomenon. This report describes an illustrative case of painful paresthesias in the territory of the ilioinguinal nerve, 3 to 6 weeks after an otherwise routine herniorraphy, which subsequently responded dramatically to carbamazepine. The case is considered in light of recent studies which have determined molecular changes which occur in dorsal root ganglion (DRG) neurons following axotomy and neuroma formation. Voltage-dependent sodium (Na+) channels in DRG neurons undergo a change following axotomy, in which there is significant up- and down-regulation of different subpopulations of Na channels over a time frame measured in days to weeks. Such changes may render the DRG neurons hyperexcitable, thus contributing to a neuropathic pain syndrome, yet susceptible to treatment with a sodium channel blocker such as carbamazepine.

Topics: Analgesics, Non-Narcotic; Axotomy; Carbamazepine; Ganglia, Spinal; Hernia, Inguinal; Humans; Inguinal Canal; Male; Middle Aged; Neuritis; Neuroma; Pain, Postoperative; Reoperation; Sodium Channels; Tetrodotoxin