Anesthesia Procedure for Congenital Insensitivity to Pain in a Child with Anhidrosis Syndrome: A Rare Case.

Congenital insensitivity to pain with anhidrosis (CIPA) syndrome is a neuropathy characterized by insensitivity to pain, impaired thermoregulation, anhidrosis, and mental retardation. A 9-year old boy with CIPA syndrome, underwent 2 operations for a calcaneal ulcer. During the first operation standard monitorization was performed. In the second operation, Bispectral Index (BIS) monitoring was added and temperature was monitored with an esophageal probe. In the first operation, in which anesthesia induction was applied with ketamine and midazolam, extremity movements with surgical stimuli were seen. Despite pain insensitivity, as extremity movements were seen with surgical stimuli, propofol was administered in the second operation. Throughout the operation, the BIS values varied from 19-58 and body temperature was measured as 36.1°C-36.9°C. In conclusion, despite the absence of pain sensitivity in CIPA syndrome cases, there is an absolute need for the administration of anesthesia in surgical procedures because of tactile hyperesthesia.

Systematic identification of proteins that elicit drug side effects.

Side effect similarities of drugs have recently been employed to predict new drug targets, and networks of side effects and targets have been used to better understand the mechanism of action of drugs. Here, we report a large-scale analysis to systematically predict and characterize proteins that cause drug side effects. We integrated phenotypic data obtained during clinical trials with known drug-target relations to identify overrepresented protein-side effect combinations. Using independent data, we confirm that most of these overrepresentations point to proteins which, when perturbed, cause side effects. Of 1428 side effects studied, 732 were predicted to be predominantly caused by individual proteins, at least 137 of them backed by existing pharmacological or phenotypic data. We prove this concept in vivo by confirming our prediction that activation of the serotonin 7 receptor (HTR7) is responsible for hyperesthesia in mice, which, in turn, can be prevented by a drug that selectively inhibits HTR7. Taken together, we show that a large fraction of complex drug side effects are mediated by individual proteins and create a reference for such relations.

Facial pain, scotomas and hemihypaesthesia as presenting symptoms of type A aortic dissection in a patient with migraine with aura.

We report the case of a 31-year-old man with a history of migraine with aura who was admitted to our emergency department because of a sudden onset of severe bilateral facial pain radiating bilaterally into the medial cervical region after defecation. The pain was accompanied by scotomas in the right visual field and hypaesthesia in both upper limbs. Imaging of the aorta and supra-aortic vessels revealed a type A aortic dissection. Subsequently, the patient received an aortic valve replacement and an aortic tube graft. After the surgery he experienced recurring visual disturbances with a sudden onset mimicking his migraine aura. Due to a new onset of atrial fibrillation, he was put on oral anticoagulants. At follow-up after 10 months he still reported episodic and mostly isolated visual auras with a gradual onset.

P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury.

Extracellular nucleotides have been implicated as signaling molecules used by microglia to sense adverse physiological conditions, such as neuronal damage. They act through purinoceptors, especially the G-protein-coupled P2Y receptor P2Y(12)R. Emerging evidence has indicated that activated spinal microglia responding to nerve injury are key cellular intermediaries in the resulting highly debilitating chronic pain state, namely neuropathic pain. However, the role of microglial P2Y(12)Rs in neuropathic pain remains unknown. Here, we show that the level of P2Y(12)R mRNA expression was markedly increased in the spinal cord ipsilateral to the nerve injury and that this expression was highly restricted to ionized binding calcium adapter molecule 1-positive microglia. An increase in the immunofluorescence of P2Y(12)R protein in the ipsilateral spinal cord was also observed after nerve injury, and P2Y(12)R-positive cells were double labeled with the microglial marker OX-42. Blocking spinal P2Y(12)R by the intrathecal administration of its antagonist AR-C69931MX prevented the development of tactile allodynia (pain hypersensitivity to innocuous stimuli), a hallmark of neuropathic pain syndrome. Furthermore, mice lacking P2ry(12) (P2ry(12)(-/-)) displayed impaired tactile allodynia after nerve injury without any change in basal mechanical sensitivity. Moreover, a single intrathecal administration of AR-C69931MX or oral administration of clopidogrel (a P2Y(12)R blocker clinically in use) to nerve-injured rats produced a striking alleviation of existing tactile allodynia. Together, our findings indicate that activation of P2Y(12)Rs in spinal microglia may be a critical event in the pathogenesis of neuropathic pain and suggest that blocking microglial P2Y(12)R might be a viable therapeutic strategy for treating neuropathic pain.

Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats.

BACKGROUND AND PURPOSE: The ability of cannabinoids to suppress mechanical hypersensitivity (mechanical allodynia) induced by treatment with the chemotherapeutic agent vincristine was evaluated in rats. Sites of action were subsequently identified. EXPERIMENTAL APPROACH: Mechanical hypersensitivity developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same times. Effects of the CB1/CB2 receptor agonist WIN55,212-2, the receptor-inactive enantiomer WIN55,212-3, the CB2-selective agonist (R,S)-AM1241, the opiate agonist morphine and vehicle on chemotherapy-induced neuropathy were evaluated. WIN55,212-2 was administered intrathecally (i.t.) or locally in the hindpaw to identify sites of action. Pharmacological specificity was established using competitive antagonists for CB1 (SR141716) or CB2 receptors (SR144528). KEY RESULTS: Systemic administration of WIN55,212-2, but not WIN55,212-3, suppressed vincristine-evoked mechanical allodynia. A leftward shift in the dose-response curve was observed following WIN55,212-2 relative to morphine treatment. The CB1 (SR141716) and CB2 (SR144528) antagonists blocked the anti-allodynic effects of WIN55,212-2. (R,S)-AM1241 suppressed vincristine-induced mechanical hypersensitivity through a CB2 mechanism. Both cannabinoid agonists suppressed vincristine-induced mechanical hypersensitivity without inducing catalepsy. Spinal sites of action are implicated in cannabinoid modulation of chemotherapy-induced neuropathy. WIN55,212-2, but not WIN55,212-3, administered i.t. suppressed vincristine-evoked mechanical hypersensitivity at doses that were inactive following local hindpaw administration. Spinal coadministration of both the CB1 and CB2 antagonists blocked the anti-allodynic effects of WIN55,212-2. CONCLUSIONS AND IMPLICATIONS: Cannabinoids suppress the maintenance of vincristine-induced mechanical allodynia through activation of CB1 and CB2 receptors. These anti-allodynic effects are mediated, at least in part, at the level of the spinal cord.

(L)-Phenylglycine, but not necessarily other alpha2delta subunit voltage-gated calcium channel ligands, attenuates neuropathic pain in rats.

Gabapentin and pregabalin have been demonstrated, both in animal pain models and clinically, to be effective analgesics particularly for the treatment of neuropathic pain. The precise mechanism of action for these two drugs is unknown, but they are generally believed to function via initially binding to the alpha2delta subunit of voltage-gated Ca2+ channels. In this study, we used a pharmacological approach to test the hypothesis whether high affinity interactions with the alpha2delta subunit alone could lead to attenuation of neuropathic pain in rats. The anti-allodynic effects of gabapentin and pregabalin, along with three other compounds--(L)-phenylglycine, m-chlorophenylglycine and 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA)--discovered to be potent alpha2delta ligands, were tested in the rat spinal nerve ligation model of neuropathic pain. Gabapentin (Ki = 120 nM), pregabalin (180 nM) and (L)-phenylglycine (180 nM) were shown to be anti-allodynic, with respective ED50 values of 230, 90 and 80 micromol/kg (p.o.). (L)-Phenylglycine was as potent as pregabalin and equi-efficacious in reversing mechanical allodynia. In contrast, two ligands with comparable or superior alpha2delta binding affinities, m-chlorophenylglycine (Ki = 54 nM) and ABHCA (150 nM), exhibited no anti-allodynic effects at doses of 30-300 micromol/kg (p.o.), although these compounds achieved substantial brain levels. The data demonstrate that, at least in the rat spinal nerve ligation model of neuropathic pain, (L)-phenylglycine has an anti-allodynic effect, but two equally potent alpha2delta subunit ligands do not. These results suggest that additional mechanisms, besides alpha2delta interactions, may contribute to the effects of compounds like gabapentin, pregabalin and (L)-phenylglycine in neuropathic pain.

Anti-allodynic and anti-hyperalgesic effects of nociceptin receptor antagonist, JTC-801, in rats after spinal nerve injury and inflammation.

The effects of nociceptin/orphanin FQ (N/OFQ) peptide receptor antagonist JTC-801 on allodynia and hyperalgesia were examined in rats in order to explore the involvement of N/OFQ system in these pathological pain states. Tactile allodynia induced by L5/L6 spinal nerve ligation was reversed by both systemic (3-30 mg/kg) and spinal (22.5 and 45 pg) JTC-801 in a dose-dependent manner. Concerning hyperalgesia induced by formalin injection into the hindpaw, JTC-801 dose-dependently suppressed the second phase, but not the first phase, of the licking behavior. Furthermore, systemic JTC-801 reduced Fos-like immunoreactivity in the dorsal horn of the spinal cord (laminae I/II). In conclusion, N/OFQ receptor antagonist JTC-801 exerted anti-allodynic and anti-hyperalgesic effects in rats, suggesting that N/OFQ system might be involved in the modulation of neuropathic pain and inflammatory hyperalgesia.

Opioids and central sensitisation: I. Preemptive analgesia.

Opioids are powerful analgesics when used to treat acute pain and some forms of chronic pain. A large body of literature has shown that opioids can, in addition, also prevent (this review) or induce and perhaps reverse, some forms central sensitisation in in vitro and in vivo animal models of pain. However, the concept of central sensitisation is, at present, ambiguous and the usefulness of opioids as preemptive analgesics in human pain patients is still not clear.

Cyclooxygenase 2 expression in the spared nerve injury model of neuropathic pain.

Cyclooxygenase-2 (COX-2) after induction peripherally, and within the CNS, plays an important role in producing inflammatory pain. However, its role in neuropathic pain models is controversial. Recently a robust and persistent model of partial nerve injury pain, the spared nerve injury (SNI) model, has been developed. The aim of the present study was to examine the regulation of COX-2 in the rat SNI model and to evaluate the effectiveness of the selective COX-2 inhibitor rofecoxib in preventing neuropathic allodynia and hyperalgesia. RNase protection assays revealed only a very small and transient increase in COX-2 mRNA in the dorsal horn of the spinal cord in the SNI model with a maximum change at 24 h. Immunohistochemical analysis showed a small increase in COX-2 protein in the deep layers of the dorsal horn 10 h following SNI surgery. Rofecoxib (100 microM) did not affect spontaneous excitatory postsynaptic currents or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propanoic acid (AMPA) and N-methyl-d-aspartate (NMDA) responses in lamina II neurons from spinal cords of animals with SNI indicating no detectable action on transmitter release or postsynaptic activity. Furthermore, rofecoxib treatment (1 and 3.2 mg/kg for 5 and 3 days respectively starting on the day of surgery) failed to modify the development of allodynia and hyperalgesia in the SNI model. However, rofecoxib significantly reduced inflammatory hypersensitivity evoked by injection of complete Freund's adjuvant into one hindpaw, indicating that the doses used were pharmacologically active. The pain hypersensitivity produced by the SNI model is not COX-2-dependent.

Key role of the dorsal root ganglion in neuropathic tactile hypersensibility.

Cutting spinal nerves just distal to the dorsal root ganglion (DRG) triggers, with rapid onset, massive spontaneous ectopic discharge in axotomized afferent A-neurons, and at the same time induces tactile allodynia in the partially denervated hindlimb. We show that secondary transection of the dorsal root (rhizotomy) of the axotomized DRG, or suppression of the ectopia with topically applied local anesthetics, eliminates or attenuates the allodynia. Dorsal rhizotomy alone does not trigger allodynia. These observations support the hypothesis that ectopic firing in DRG A-neurons induces central sensitization which leads to tactile allodynia. The question of how activity in afferent A-neurons, which are not normally nociceptive, might induce allodynia is discussed in light of the current literature.

Formalin-induced central sensitization in the rat: somatosensory evoked potential data.

Cortical somatosensory evoked potentials were used to measure secondary hyperaesthesia resulting from subcutaneous 1 and 5% formalin in unanesthetized rats with permanently implanted electrodes. Near field responses were evoked by contralateral non-noxious electrical stimulation of the middle third of the tail. 0.05 ml 5% formalin injected subcutaneously at the base of the tail increased the amplitude of P1-N1 a maximum of 158.5+/-10.91% and N2 a maximum of 150.4+/-21.40% compared to controls (P<0.05 and P<0.01). Amplitudes were increased from 5 min after injection to the end of the 70 min test period. The effect of 1% formalin was equivalent to 5% formalin. This increase was prevented by pretreatment with 5 mg/kg ketamine or 5 mg/kg morphine, in agreement with behavioral and electrophysiological data. Cortical somatosensory evoked potentials are objective measures of central sensitization which may usefully complement current behavioral models for the evaluation of analgesic drugs.

Clonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects.

Antagonists of NMDA glutamate receptors have been shown to alleviate neuropathic pain in rats and humans. However, NMDA antagonists can cause significant side effects ranging from behavioral disturbances to injury of neurons in the posterior cingulate/retrosplenial (PC/RS) cortex. We have found that alpha-2 adrenergic agonists prevent the PC/RS neurotoxic side effects of NMDA antagonists. In the present study of adult female rats subjected to sciatic nerve ligation (Bennett neuropathic pain model) and tested for paw withdrawal latency (PWL) following a thermal stimulus, we evaluated the ability of the NMDA antagonist, MK-801, to alleviate neuropathic pain either by itself or when administered together with the alpha-2 adrenergic agonist, clonidine. We found that MK-801, at a dose (0.05 mg/kg s.c.) that is known to cause mild hyperactivity but is subthreshold for producing PC/RS neurotoxic changes, relieved the neuropathic pain state associated with sciatic nerve ligation. However, the relief at this dose was very transient, and no neuropathic pain-relieving effect was observed at a lower dose (0. 025 mg/kg s.c.) of MK-801. Clonidine, at a dose (0.05 mg/kg s.c.) that prevents the cerebrocortical neurotoxic effects of MK-801, decreased sensitivity to the thermal stimulus equally under all conditions (ligated, sham ligated, unoperated), but did not specifically relieve neuropathic pain in the ligated limb. Combining this dose of clonidine with an ineffective dose (0.025 mg/kg s.c.) of MK-801 provided specific, complete and long lasting (up to 4 h) relief from neuropathic pain. Rats receiving this drug combination did not display hyperactivity or any other behavioral disturbance typically associated with MK-801 treatment, nor show neurotoxic changes in cerebrocortical neurons. In separate experiments on normal unoperated rats, we found that clonidine (0.05 mg/kg s.c.) counteracted the hyperactivity induced by MK-801 (0.05 mg/kg s.c.) and returned activity levels to a normal range. These findings signify that clonidine, which does not specifically relieve neuropathic pain, can potentiate the neuropathic pain-relieving action of MK-801, while also protecting against neurotoxicity and hyperactivity side effects of MK-801. The potentiation is of a sufficient magnitude that it permits cutting the MK-801 dose requirement in half, thereby achieving prolonged neuropathic pain relief while doubling the margin of safety against any type of side effect that might be mediated by blockade of NMDA receptors.

Clonidine, but not morphine, delays the development of thermal hyperesthesia induced by sciatic nerve constriction injury in the rat.

BACKGROUND: It has been shown that the spinal facilitation induced by the injury discharge evoked by a nerve constriction injury is crucial in the development of thermal hyperesthesia. Both opioids and alpha 2 agonists have been reported to prevent the development of spinal facilitation evoked by the small afferent input to the spinal cord. Moreover, it has been reported that the thermal hyperesthesia induced by a nerve constriction injury is sympathetically maintained and that spinally administered alpha 2 agonists can modulate the sympathetic outflow from the spinal cord. The current study investigated the effect of spinally administered morphine and clonidine, an alpha 2 agonist, on the development of thermal hyperesthesia induced by nerve constriction injury in the rat. METHODS: A model of thermal hyperesthesia induced by a constriction injury created by making four loose ligatures around the rat sciatic nerve was used to examine the development of thermal hyperesthesia. Morphine, clonidine, and idazoxan were administered intrathecally or intraperitoneally 20 min before (pretreatment study) or 20 min after (posttreatment study) the nerve injury. RESULTS: Pretreatment, but not posttreatment, with intrathecal clonidine significantly delayed the development of thermal hyperesthesia in a dose-dependent manner, and this delay in onset produced by clonidine was 3 days after the nerve injury. This effect of clonidine's was completely antagonized by the coadministration of idazoxan with clonidine. Intrathecal morphine had no effect on the development of thermal hyperesthesia in this study. CONCLUSIONS: Spinal alpha 2 receptors, but not opioid receptors, may play an important role in the development of thermal hyperesthesia induced by a nerve constriction injury. This suggested that the activation of spinal alpha 2 receptor may reduce the sympathetic outflow and this reduction of sympathetic outflow may be the key mechanism that delays the development of thermal hyperesthesia.

Bradykinin-induced sensitization of afferent neurons in the rat paw.

Determination of the thermal nociceptive threshold in the rat hind paw was used to investigate the participation of postganglionic sympathetic neurons and of capsaicin-sensitive afferent neurons to bradykinin-induced thermal hyperaesthesia. Intraplantar injection of 0.5 microgram bradykinin or of 0.3 microgram prostaglandin E2 significantly lowered paw withdrawal latencies, whereas injection of [des-Arg9]bradykinin was ineffective. The B-2 receptor antagonist HOE 140 (0.1 mg/kg) prevented bradykinin- but not prostaglandin E2-induced thermal hyperaesthesia. While morphine (1 mg/kg) antagonized the effect of bradykinin and prostaglandin E2, indomethacin (10 mg/kg) reduced only bradykinin-induced sensitization. Although this can be taken as indication that bradykinin-induced sensitization of heat-sensitive fibres is mainly mediated via local prostanoid formation, we failed to obtain evidence for an involvement of sympathetic postganglionic fibres in this process: chemical sympathectomy, which lowered the tissue concentration of noradrenaline by more than 90%, did not influence the ability of bradykinin to induce a decrease in thermal nociceptive threshold. The target of bradykinin/prostaglandin E2 action seemed to be capsaicin-sensitive afferents, since in rats which had been treated with capsaicin to destroy this group of afferents, both substances were completely ineffective in producing sensitization. We suggest therefore that in the rat paw, bradykinin, independently from sympathetic postganglionic neurons, lowers the thermal nociceptive threshold mainly via B-2 receptor-mediated formation of cyclo-oxygenase products which, in turn, act exclusively on capsaicin-sensitive afferent neurons.

Role of the injury discharge in the development of thermal hyperesthesia after sciatic nerve constriction injury in the rat.

BACKGROUND: Usually, a barrage of impulses ("injury discharge") is evoked following sensory nerve damage. It has been suggested that injury discharge may produce the hyperexcitatory state in the spinal cord, and this hyperexcitability may cause neurogenic pain. In the present study, the authors examined the role of injury discharge in developing the hyperesthetic state following nerve constriction injury. METHODS: A model of thermal hyperesthesia caused by a constriction injury created by making four loose ligations around the rat sciatic nerve was examined. To block the injury discharge, 0.5% bupivacaine was applied to the sciatic nerve before constriction injury. To block the hyperexcitatory state, (+)-MK-801, an N-methyl-D-aspartate antagonist, was administered intrathecally 15 min before the nerve lesion. RESULTS: Blocking injury discharge significantly delayed the development of hyperesthesia. Bupivacaine had no effect on the development of hyperesthesia when bupivacaine was applied to the sciatic nerve 15 min after the nerve constriction injury. Systemic bupivacaine had no effect on the development of thermal hyperesthesia. Intrathecal (+)-MK-801 also delayed the development of hyperesthesia when (+)-MK-801 was administered intrathecally 15 min before the nerve injury. When (+)-MK-801 was administered 15 min after the nerve injury, (+)-MK-801 had no effect on the development of hyperesthesia. CONCLUSION: These results suggest that injury discharge may induce facilitation of spinal dorsal horn neurons, and this spinal facilitation may play an important role in developing thermal hyperesthesia following sciatic nerve constriction injury.

The antiinflammatory profile of (5H-dibenzo[a,d]-cyclohepten-5-ylidene)acetic acid (WY-41,770), an agent possessing weak prostaglandin synthetase inhibitory activity that is devoid of gastric side effects.

Wy-41,770 [(5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid], a novel acrylic acid, was compared to indomethacin and aspirin in standard antiinflammatory, analgesic and antipyretic animal models. The acute antiinflammatory, analgesic and antipyretic activity of Wy-41,770 (oral ED50S 50-170 mg/kg) was similar to aspirin; however, it was considerably more potent orally in adjuvant arthritis in the rat (ED50, 16 mg/kg) and urate-induced synovitis in the dog (ED50, 4.5 mg/kg). Wy-41,770 was a weak inhibitor of prostaglandin biosynthesis and did not inhibit either 5- or 15-lipoxygenase. Furthermore, the cellular migration characteristic of carrageenan pleurisy was not affected by Wy-41,770. Unlike a majority of NSAIDs, it produced no gastric irritation in rats after either acute or chronic oral administration over the range 400-800 mg/kg. The major mechanism of action of Wy-41,770 has yet to be identified but does not seem to involve interference of arachidonic acid metabolism.