Wiliam A. Prado

The dual effect of a nitric oxide donor in nociception.

Low intrathecal (i.t.) doses of the nitric oxide (NO)-donor 3-morpholinosydnonimine (SIN-1) (0.1-2.0 microg/10 microl) reduced, while higher doses had no effect (5 or 100 microg/10 microl) or increased (10 and 20 microg/10 microl) the mechanical allodynia induced by chronic ligature of the sciatic nerve in rats. SIN-1 (0.1-100 microg/10 microl; i.t.) produced only antinociceptive effect in the rat tail flick test. The inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (4 microg/10 microl; i.t.), abolished the antinociceptive effects of SIN-1 in both tests and reduced the effect of high doses of SIN-1 in neuropathic rats. Hemoglobin (100 microg/10 microl; i.t.), a NO scavenger, inhibited the effect of low dose of SIN-1 and reduced the effect of high dose of SIN-1 in neuropathic rats. 8-Bromo-cGMP (125-500 microg/10 microl; i.t.), reduced the mechanical allodynia in neuropathic rats. The NO-synthase inhibitors, NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) (75-300 microg/10 microl; i.t.) reduced the mechanical allodynia evoked by nerve injury and increased the tail-flick latency, respectively. These effects were reduced and inhibited, respectively, by previous i.t. ODQ. The effect of L-NOARG was enhanced in a non-significant manner by hemoglobin. These results indicate that SIN-1 and NO-synthase inhibitors reduce pain through a spinal mechanism that involves activation of guanylate cyclase. The effects of SIN-1 vary depending on the dose and pain model utilized, but its most sensitive effect seems to be antinociception. However, high doses of the NO-donor can intensify ongoing pain.

The effects of early or late neurolytic sympathetic plexus block on the management of abdominal or pelvic cancer pain

&NA; Neurolytic sympathetic plexus block (NSPB) has been proposed to prevent the development of pain and improve the quality of life of patients with cancer, thus questioning the WHO protocol that proposes the use of invasive methods only as a final resort. This study evaluates the pain relief, opioid consumption and quality of life provided by the use of NSPB in two different phases of cancer pain and compares them with that provided by pharmacological therapy only. Sixty patients with abdominal or pelvic cancer pain were divided into three groups and observed for 8 weeks. In group I, neurolytic celiac (NCPB) or superior hypogastric plexus block (SHPB), or lumbar sympathetic ganglion chain block (LSGCB) was performed with alcohol in patients using NSAID and a weak oral opioid or morphine (dose≤90 mg/day) and reporting VAS≥4. In group II, NCPB, SHPB or LSGCB were performed on patients using NSAID and morphine (dose≥90 mg/day) and reporting VAS≥4. The patients of group III received pharmacological therapy only. The patients of groups I and II had a significant reduction of pain (P<0.004), opioid consumption (P<0.02) and a better quality of life (P<0.006) than those of group III, but no significant differences between groups I and II were seen in these aspects. Opioid‐related adverse effects were significantly greater in group III (P<0.05). The occasional neurolysis‐related complications were transitory. The results suggest NSPB for the management of cancer pain should be considered earlier in the disease.

Analgesia Induced by 2- or 100-Hz Electroacupuncture in the Rat Tail-Flick Test Depends on the Activation of Different Descending Pain Inhibitory Mechanisms

UNLABELLED We evaluated the effectiveness of intrathecal antagonists of α1- (WB4101) and α2- (idazoxan) adrenoceptors and serotonergic (methysergide), opioid (naloxone), muscarinic (atropine), GABA(A) (bicuculline) and GABA(B) (phaclofen) receptors in blocking 2- or 100-Hz electroacupuncture (EA)-induced analgesia (EAIA) in the rat tail-flick test. EA was applied bilaterally to the Zusanli and Sanyinjiao acupoints in lightly anesthetized rats. EA increased tail-flick latency, where the effect of 2-Hz EA lasted longer than that produced by 100-Hz EA. The 2-Hz EAIA was inhibited by naloxone or atropine, was less intense and shorter after WB4101 or idazoxan, and was shorter after methysergide, bicuculline, or phaclofen. The 100-Hz EAIA was less intense and shorter after naloxone and atropine, less intense and longer after phaclofen, shorter after methysergide or bicuculline, and remained unchanged after WB4101 or idazoxan. We postulate that the intensity of the effect of 2-Hz EA depends on noradrenergic descending mechanisms and involves spinal opioid and muscarinic mechanisms, whereas the duration of the effect depends on both noradrenergic and serotonergic descending mechanisms, and involves spinal GABAergic modulation. In contrast, the intensity of 100-Hz EAIA involves spinal muscarinic, opioid, and GABA(B) mechanisms, while the duration of the effects depends on spinal serotonergic, muscarinic, opioid, and GABA(A) mechanisms. PERSPECTIVE The results of this study indicate that 2- and 100-Hz EA induce analgesia in the rat tail-flick test activating different descending mechanisms at the spinal cord level that control the intensity and duration of the effect. The adequate pharmacological manipulation of such mechanisms may improve EA effectiveness for pain management.

Role of PAG in the antinociception evoked from the medial or central amygdala in rats

The effects of stimulating the periaqueductal gray (PAG) against the rat tail flick reflex (TFR) was not changed significantly by the microinjection of lidocaine (5%/0.5 microl) into the medial (ME) or central (CE) nuclei of the amygdala. In contrast, lidocaine into the PAG blocked the effects from the ME or CE. The microinjection of naloxone (1 microg), beta-funaltrexamine (2 microg), propranolol (1 microg), or methysergide (1 microg), but not atropine (1 microg) or mecamylamine (1 microg) into the PAG significantly reduced the effects from the CE. The effect from the ME was not altered significantly by microinjecting naloxone into the PAG. Therefore, the ME or CE are unlikely to be intermediary stations for depression of the TFR evoked by stimulating the PAG, but the PAG may be a relay station for the effects of stimulating the ME or CE. The circuitry activated from the CE, but not the ME, utilises opioid mediation in the PAG. The effect from the CE depends at least on mu-opioid, serotonergic, and probably beta-adrenergic mediation in the PAG.

A new role for the renin—angiotensin system in the rat periaqueductal gray matter: Angiotensin receptor-mediated modulation of nociception

Renin-angiotensin (Ang) system (RAS) peptides injected into the periaqueductal gray matter (PAG) elicit antinociception. Saralasin blocks Ang II-elicited antinociception. Thus, it is possible that endogenous RAS peptides could participate on the modulation of nociception in the PAG. This possibility was tested here injecting, in the PAG, the specific Ang type 1 and type 2 receptor (AT1 receptor and AT(2 receptor) antagonists losartan and CGP42,112A, respectively, either alone or before Ang II. The effects of Ang II, losartan and CGP42,112A on nociception were measured using the tail flick test and the model of incision allodynia. Ang II increased tail-flick latency, an effect inhibited by both losartan and CGP42,112A. Ang II reduced incisional allodynia. Either losartan or CGP42,112A alone increased incision allodynia, suggesting that endogenous Ang II and/or an Ang-peptide participates in the control of allodynia by the PAG. AT1 and AT2 receptors were immunolocalized in neuronal cell bodies and processes in the ventrolateral PAG. Taken together, the antinociceptive effect of Ang II injection into the ventrolateral PAG, the increase of allodynia elicited by injecting either losartan or CGP42,112A alone in the PAG, and the presence of AT1 and AT2 receptors in neurons and neuronal processes in the same region, represent the first evidence that part of the tonic nociceptive control mediated by the PAG is carried out locally by endogenous Ang II and/or an Ang-peptide acting on AT1 and AT2 receptors.

Intrathecal neostigmine for postoperative analgesia after orthopedic surgery

STUDY OBJECTIVE To establish a dose-response curve for the analgesic effect of intrathecal neostigmine in patients undergoing below knee surgery with spinal anesthesia. To assess adverse effects, principally nausea and vomiting. DESIGN Randomized, double-blind, prospective study. SETTING Teaching hospital. PATIENTS 60 ASA physical status I and II premedicated patients undergoing orthopedic surgery (tibial or ankle reconstruction). INTERVENTION Spinal anesthesia was performed at the sitting position, L3-L4 interspace, 4 ml final volume, injected at a rate of 1 ml/10 sec. The control group (CG) received 15 mg hyperbaric bupivacaine 0.5% plus saline. The 25 micrograms neostigmine group (25NG) received 15 mg hyperbaric bupivacaine plus 25 micrograms neostigmine; the 50 micrograms neostigmine group (50NG) received 15 mg hyperbaric bupivacaine plus 50 micrograms neostigmine; and the 100 micrograms neostigmine group (100NG) received 15 mg hyperbaric bupivacaine plus 100 micrograms neostigmine. Patients were placed supine after the spinal punction. MEASUREMENTS AND MAIN RESULTS Time to first rescue analgesics, analgesia, and adverse effects at constant intervals were assessed using the 10 cm visual analog scale (VAS). Intrathecal neostigmine produced a dose-independent reduction in the postoperative rescue analgesic consumption (p < 0.0001). The time to first rescue analgesics was similar among groups (p > 0.05), and the overall 24-hour VAS pain scores were lowest for patients who had spinal neostigmine (p < 0.02). The 100NG group had the highest incidence of postoperative nausea and vomiting of all the groups (p < 0.05). CONCLUSION Intrathecal neostigmine produced a dose-independent analgesia and a dose-dependent incidence of adverse effects with the doses studied.

Antinociception induced by intraperitoneal injection of gentamicin in rats and mice

&NA; Intraperitoneal administration of gentamicin sulfate (5–800 &mgr;g/kg), but not gentamicin base (23–92 &mgr;g/kg) produced antinociception in rats and mice, as assessed by the tail‐flick, carrageenan‐induced articular incapacity tests, and hot‐plate tests. The AD50 s in rats (tail‐flick test) and mice (hot‐plate test) were 11.48 and 147.9 &mgr;g/kg, respectively, but doses of 200–800 &mgr;g/kg were required to reduce the hyperalgesia induced in rats by carrageenan. In both species, bell‐shaped dose‐response curves were obtained, indicating that high doses of gentamicin had little or no effect. Non‐effective doses of gentamicin failed to produce a significant increase in morphine antinociception in either rodent species. The possible involvement of N‐type voltage‐sensitive. Ca2+ channels in the mechanism of antinociception induced by gentamicin is considered.

Analgesic effect of subarachnoid neostigmine in two patients with cancer pain

&NA; Two patients suffering with severe pain due to metastatic abdominal neoplasm were selected to examine whether subarachnoid neostigmine provided effective pain relief. Neostigmine was injected through a catheter introduced into the subarachnoid space at L4–L5. Patients were monitored for changes in arterial blood pressure, cardiac and respiratory rates, body temperature, level of consciousness and neurologic change. Pain was classified by the patients on a verbal four‐grade scale, and analgesia was classified on a verbal three‐grade scale. Complete pain relief was obtained 2 h after neostigmine (0.2 mg) in one patient and 4 h after neostigmine (0.1 mg) in the second patient. Pain of mild intensity returned 20 and 22 h after drug administration, respectively. Gastrointestinal discomfort was observed in both cases, but nausea and vomiting occurred only in the patient treated with the highest dose of neostigmine. No significant change in the monitored parameters was observed, except for a 6‐h period of decreased blood pressure in the patient treated with the lower dose of neostigmine which required no specific treatment. The results obtained in these anecdotal cases indicate that subarachnoid neostigmine may provide analgesia in patients with pain arising from neoplasia, but further studies using controlled trials are needed before the drug is brought into clinical use.

Pharmacological and neuroanatomical evidence for the involvement of the anterior pretectal nucleus in the antinociception induced by stimulation of the dorsal raphe nucleus in rats

&NA; Several studies have shown that the anterior pretectal nucleus (APtN) is involved in descending inhibitory pathways that control noxious inputs to the spinal cord and that it may participate in the normal physiological response to noxious stimulation. Among other brain regions known to send inputs to the APtN, the dorsal column nuclei (DCN), pedunculopontine tegmental nucleus (PPTg), deep mesencephalon (DpMe), and dorsal raphe nucleus (DRN) are structures also known to be involved in antinociception. In the present study, the effects of stimulating these structures on the latency of the tail withdrawal reflex from noxious heating of the skin (tail flick test) were examined in rats in which saline or hyperbaric lidocaine (5%) was previously microinjected into the APtN. Brief stimulation of the PPTg, DpMe or DRN, but not the DCN, strongly depressed the tail flick reflex. The antinociceptive effect of stimulating the DRN, but not the PPTg or DpMe was significantly reduced, but not abolished, by the prior administration of the local anaesthetic into the APtN. The antinociception induced by stimulation of the PPTg or DpMe, therefore, is unlikely to depend on connections between these structures and the APtN. Similar inhibition of the effect of stimulating the DRN was obtained from rats previously microinjected with naloxone (2.7 nmol) or methysergide (2 nmol) into the APtN. Strongly labelled cells were identified in the DRN following microinjection of the fluorescent tracer Fast Blue into the APtN. These results indicate that the APtN may participate as a relay station through which the DRN partly modulates spinal nociceptive messages. In addition, they also indicate that endogenous opioid and serotonin can participate as neuromodulators of the DRN‐APtN connection.

Involvement of the anterior pretectal nucleus in the control of persistent pain: a behavioral and c-Fos expression study in the rat.

&NA; The anterior pretectal nucleus (APtN) participates in nociceptive processing and in the activation of central descending mechanisms of pain control. In this study we used behavioral tests (incisional pain and carrageenan‐induced inflammatory pain) and c‐Fos expression changes to examine the involvement of the APtN in the control of persistent pain in rats. A 1 cm longitudinal incision through the skin and fascia of the plantar region (large incision), or a 0.5 cm longitudinal incision through the skin only (small incision) was used, and the postoperative incisional allodynia was evaluated with von Frey filaments. The hyperalgesia produced by the intraplantar administration of carrageenan (25 or 50 &mgr;g/100 &mgr;l) into a hind paw was evaluated by a modified paw pressure test. The electrolytic lesion of the contralateral, but not ipsilateral, APtN significantly intensified the allodynia produced by a large incision of the hind paw. The incisional allodynia and the carrageenan‐induced hyperalgesia were intensified by the microinjection of 2% lidocaine into the contralateral, but not ipsilateral APtN, the effect being significantly stronger when a large incision or a higher carrageenan concentration was utilized. A significant increase in the number of c‐Fos positive cells was found in the ipsilateral, and mainly in the contralateral APtN of rats submitted to a large incision. The number of positive cells in the superficial or deep laminae of the contralateral spinal cord of control and incised rats was not significantly different. Positive cells in the superficial or deep laminae of the ipsilateral spinal cord were significantly more numerous than in control, the effect being significantly more intense in rats with large incision. The microinjection of 0.5% bupivacaine into the APtN contralateral to the incised hind paw reduced the number of positive cells bilaterally in the APtN, but the effect was significant in the contralateral nucleus only. The number of positive cells in the superficial and deep laminae of the contralateral spinal cord of incised and non‐incised animals was not significantly changed by the neural block of the contralateral APtN. In the ipsilateral spinal cord, the incision‐induced increase in the number of positive cells was significantly reduced in the superficial lamina and significantly increased in the deep lamina of animals previously treated with bupivacaine in the contralateral APtN. In conclusion, the integrity of the APtN is necessary to reduce the severity of the responses to persistent injury. The results also are in agreement with the current notion that persistent noxious inputs to the APtN tonically activate a descending mechanism that excites superficial cells and inhibits deep cells in the spinal dorsal horn.