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PubMed1997

Effects of chemical stimulation of masseter muscle nociceptors on trigeminal motoneuron and interneuron activities during fictive mastication in the rabbit.

An electrophysiological study was carried out in sixteen decerebrate and paralyzed New Zealand rabbits to determine how a bolus injection of a nociceptor stimulant (hypertonic saline, 5%) into the masseter muscle influences the activity of the trigeminal motor circuitry during fictive jaw movements. Hypodermic needles connected to a syringe held in a computer-controlled infusion pump were inserted into the anterior deep layer of either the right or the left masseter. Twenty-three infusions of 50, 70 or 80 microl saline were made in fourteen animals at constant rates over 1 min. Eight control infusions of normal saline (0.9%) were made in a subpopulation of five animals in an identical manner. Fictive jaw movements were evoked before and after the infusions by repetitive electrical stimulation of the corticobulbar tract. Effects were assessed by extracellular microelectrode recordings made from the digastric motoneuron pool and from putative last-order interneurons in the oral subnucleus of the spinal trigeminal tract and adjacent structures. In comparison with pre-infusion control cycles, nociceptor stimulation caused significant slowing of the rhythm and a reduction of the area of the digastric motoneuron bursts in the majority of the animals (12/14). The decrease in cycle frequency was due almost entirely to a lengthening of the time between the digastric bursts. Changes usually began 1-2 min after the infusion and returned to pre-infusion values within 10-15 min. No significant effects were seen when isotonic saline was applied. Recordings were obtained from nine interneurons, eight of which had low threshold mechanosensitive receptive fields. One neuron was, in addition, excited by pinch. Eight were not active in the absence of motor activity and this did not change when hypertonic saline was applied. However, once fictive movements began, all started to fire rhythmic bursts of spikes. In five cases, there was a significant post-infusion increase in spike frequency, and three showed decreases. Seven showed significant post-infusion changes in mean phase and/or concentration of their firing within the movement cycle. Changes in the preferred phase of interneuronal firing were significantly correlated to changes in the phase of offset of the digastric burst. The present results provide evidence that the stimulation of nociceptors in a muscle slows the frequency of rhythmical movements in the absence of sensory feedback. They confirm that infusions into one muscle affect the output of its antagonist. The results also suggest that neurons in the oral subnucleus of the spinal trigeminal tract and adjacent reticular formation appear to participate in programming these changes in motor output.

Animals↗
PubMed2003

Prevention of postoperative nausea and vomiting after spinal morphine for Caesarean section: comparison of cyclizine, dexamethasone and placebo.

BACKGROUND: Low-dose intrathecal (spinal) morphine (0.1-0.2 mg) for Caesarean section delivers excellent postoperative analgesia but is associated with significant nausea and vomiting. We compared the antiemetic efficacy of cyclizine, dexamethasone, and placebo in this clinical setting. METHODS: Ninety-nine women undergoing elective Caesarean section under spinal anaesthesia were allocated randomly, in a double-blind study design, to receive either cyclizine 50 mg, dexamethasone 8 mg, or placebo as a single-dose infusion in saline 0.9%, 100 ml on completion of surgery. Spinal anaesthesia consisted of: hyperbaric bupivacaine 0.5%, 2.0 ml; fentanyl 10 micro g; and spinal morphine 0.2 mg. The primary outcome measure was the incidence of nausea. RESULTS: The incidence of nausea was significantly less in patients receiving cyclizine compared with dexamethasone and placebo (33 vs 60 and 67%, respectively, P<0.05). Severity of nausea and number of vomiting episodes were also less at 3-6 h in cyclizine patients. Overall satisfaction with postoperative care at 24 h, expressed on a 100 mm visual analogue scale, was greater in cyclizine [78 (28)] than either dexamethasone [58 (31), P=0.03] or placebo [51 (28), P=0.008]. CONCLUSION: We conclude that following spinal morphine 0.2 mg and fentanyl 10 micro g analgesia for Caesarean section, cyclizine 50 mg i.v. reduces the incidence of nausea compared with dexamethasone 8 mg i.v. or placebo. It also lessens the severity of nausea and vomiting, and increases maternal satisfaction in the early postoperative period.

Adult↗
PubMed1997

Adenosine for pain control.

The antinociceptive actions of adenosine and adenosine analogs in animal models has been known for more than 10 years. The recent development with regard to the pain modulatory effects of adenosine, primarily in clinical studies, has generated a renewed interest in this principle for pain control. This review summarizes the current knowledge in adenosine mediated pain modulation in acute and chronic conditions, with focus on studies in man. The endogenous compound adenosine has various modulatory effects in the peripheral and central nervous system, mediated through specific cell-surface associated receptors. The current view is that adenosine receptors of the A1-subtype are associated with a modulatory effect on pain transmission at spinal cord level. Animal studies have repeatedly demonstrated adenosine- and adenosine analog mediated inhibitory influences on presumed nociceptive reflex responses (1,2). These examinations in rodents have tested acute pain models involving tactile, pressure and heat stimulations. More recently, animal lesion models presumably reflecting chronic pain, has shown that adenosine analogs can suppress nociceptive behaviour both by systemic and intrathecal (i.t.) administration (3,4). Consequently, there is substantial evidence that adenosine can modulate nociceptive input. Further, it has been proposed that endogenous adenosine formation is involved in physiological pain control at the spinal cord level and that its release is involved in the action of opioid antinociception (1). Clinical studies have revealed that adenosine administration by bolus injection or by infusion at doses above 70 micrograms x kg-1 x min-1 is associated with pain symptoms from different parts of the body. This algogenic effect of higher doses of adenosine is probably related to sensitization/activation of peripheral nociceptive afferents (5).

Acute Disease↗
PubMed2005

Early protective effects of iloprost, a stable prostacyclin analog, during spinal cord ischemia in a rabbit model.

Spinal cord ischemia may develop into paraplegia in some cases during operation of the thoracoabdominal aorta. This is attributable to the vulnerability of spinal motor neurons to ischemia. In this study, iloprost was used as an agent to decrease the severity of ischemia and reperfusion injury to the spinal cord motor neurons. Twenty-one rabbits were randomized into three groups of seven animals each: group A (iloprost not administered), group B (25 ng/kg per minute iloprost), and group S (sham-operated). The spinal cord ischemia model was created by a 15-min occlusion of the aorta just caudal to the renal artery with a balloon catheter. Administration of iloprost began 10 min before occlusion of the aorta, and continued thereafter for 60 min. The pre- and postocclusion arterial pressure and heart rate recordings, results of blood gas analyses, and hematocrit and glucose levels were recorded. The spinal cords were removed after 8-h monitoring of neurologic function. Viable and nonviable motor neurons in the anterior horn of the spinal cord were counted under light microscopy. Any significant alteration in hemodynamics, blood gases, and other physiologic parameters could not be detected within the groups. Iloprost had a moderately hypotensive effect. Neurologic function in terms of Johnson scoring was significantly better in the iloprost group (P<0.05). The number of viable cells was higher, whereas the number of nonviable cells was lower in iloprost group, when compared with the control group (P<0.05). Higher numbers of viable motor neurons were consistent with the neurological findings. As a result of this study we concluded that iloprost infused during clamping of the aorta mitigates the spinal cord injury due to ischemia and reperfusion, and has a significant protective effect.

Animals↗
PubMed1993

Spinal cord blood flow and evoked potential responses after treatment with nimodipine or methylprednisolone in spinal cord-injured rats.

This study examined the effect of nimodipine or methylprednisolone on spinal cord blood flow (SCBF) and electrophysiological function after spinal cord injury in rats. Three groups of male rats (n = 10 per group) were injured by compression of the cord at T1 for 1 minute with a 52-g clip. The hydrogen clearance technique was used to measure SCBF at the T1 segment. Motor and somatosensory evoked potentials were recorded. SCBF and evoked potentials were measured before injury and again at approximately 1 and 2.5 hours after injury. The methylprednisolone group received a bolus of methylprednisolone (30 mg/kg) at 5 minutes after injury and then at 15 minutes after injury, the group received an infusion of methylprednisolone at 5.4 mg/kg per hour. The nimodipine group received placebo at 5 minutes and then received an infusion of nimodipine at 0.02 mg/kg per hour at 15 minutes. The placebo group received placebo at both times. Physiological parameters were closely monitored and maintained within the normal range. Albumin was administered after injury to maintain mean arterial blood pressure at or above 80 mm Hg. The infusions were continued for approximately 3 hours after spinal cord injury. SCBF was not significantly different between the experimental groups at either 1 or 2.5 hours postinjury (P = 0.16 and 0.71, respectively), and evoked potential responses did not return in any rat at any time after injury. Thus, this experiment failed to demonstrate an improvement in SCBF or electrophysiological function with either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Reduced spinal reflexes following intrathecal baclofen in the rabbit.

Intrathecal baclofen is effective in reducing polysynaptic spinal reflexes in awake rabbits. A single lumbar infusion of 2.5-5.0 ng drug caused a significant reduction in the crossed extensor response to electrical stimulation of the plantar surface of the hindlimb. This inhibition lasted 5 h or more. At doses of 3 micrograms or less, the forelimbs were unaffected.

Animals↗
PubMed1987

[Ephedrine administration for cesarean section under spinal anesthesia].

Prophylactic ephedrine was administered to healthy parturients undergoing elective cesarean section under spinal anesthesia. The methods of ephedrine administration were as follows: intramuscular injection of 0.3 mg/kg, 15 minutes before the block (20 cases: group M), infusion of 0.02% solution immediately after the block (20 cases: group D), premedication with atropine 0.5 mg and infusion immediately after the block (20 cases: group AD). The mean ephedrine dosage was 18.8 +/- 2.2 gm (SD) in group M, 12.6 +/- 6.2 mg in group D and 5.2 +/- 0.7 mg in group AD, and there were significant differences among the three groups. The base line (a), the minimal postanesthetic (b) and the maximal postpartum systolic blood pressures (c) revealed no significant difference among the three groups, and 'b' was significantly higher than 'a' and lower than 'c' in all groups. Only one case (group M) was transiently hypotensive, while hypertension was not found in any of the subjects. One- and 5-minute Apgar scores were 8 or more in all, and umbilical acid-base values were within normal limits in all of them, though the base deficit in group AD was significantly lower than that in group M. Atropine premedication makes it possible to retrench the ephedrine dosage without any harmful effect on either mother or fetus, and ephedrine infusion makes it easy to cope with changes in maternal blood pressure. Consequently, for healthy parturients receiving elective cesarean section under spinal block, we recommend atropine premedication and minimal infusion of ephedrine immediately following the block.

Adult↗
PubMed1995

Implants for spasticity.

In carefully selected groups of patients, intrathecal baclofen therapy offers well-proven benefits in reducing spasticity, notably in cases of spinal injury and multiple sclerosis. The initial costs of implantation are high, and there must be a long-term commitment by both patient and medical personnel to careful and proper management. Nevertheless, in suitable cases, the techniques should generally be properly considered before proceeding to any irreversible destructive neurosurgical procedure.

Baclofen↗
PubMed2004

[Implantable drug pumps for spinal opioid analgesia: technical solutions and problems].

Among the many technical appliances for pain therapy which are currently available, the use of implantable drug pumps for prolonged pain treatment is of increasing importance. Since this kind of pain therapy can be used without any problems outside the hospital, it improves the quality of life of the patient. Furthermore, it is combined with a reduction of side-effects which frequently occur when analgesics are given orally or parenterally in big single doses. High initial costs are compensated by a good cost-benefit ratio of this kind of pain treatment, which enables the use of analgesics in low doses in out-patients. Based on the use of gas mixtures which can be compressed repeatedly, implantable mechanically-driven pumps are a nearly inexhaustible propulsion unit for drug infusions. The development of new gas mixtures and of innovative control mechanisms allows greater independence from surrounding influences and higher precision regarding infusion rates. Mechanically-driven pumps are characterized by prolonged functioning and low cost of purchase. Therefore, they will continue to be available on the medical market in future. Special progress in cardiac pacemaker therapy as well as further miniaturization of portable infusion pumps with peristaltic propulsion have led to the development of programmed implantable pumps with lithium batteries as energy sources. The advantages of these pumps, particularly those with "externally" programmable infusion rates (continuous, bolus, periodical bolus, etc.) point to the future. With these devices, evacuation and refilling of the pumps due to necessary changes of drug concentrations, as has to be done with mechanically working pumps with fixed infusion rates, are no longer necessary. Therefore, these programmable pumps can also be used for infusion of drug concentrates. At present, however, high costs and the battery-dependent limited duration of functioning of these devices are disadvantageous. As with cardiac pacemakers, battery exchange is necessary. Using implantable drug pumps, relevant changes of body temperature and atmospheric pressure lead to more or less considerable deviations of the infusion rates. These deviations differ from product to product and can be studied in the informative material published by the manufacturer.

Analgesics, Opioid↗
PubMed2003

The site of action of epidural fentanyl in humans: the difference between infusion and bolus administration.

UNLABELLED: Most published studies suggesting that epidural fentanyl acts predominantly at spinal sites administered the drug as a bolus injection, whereas most studies suggesting that it acts predominantly at supraspinal sites administered the drug as an infusion. In this study we tested the hypothesis that the mode of administration (bolus versus infusion) of epidural fentanyl determines its site of action. Ten healthy volunteers were enrolled in this randomized, double-blinded, cross-over study. On separate study days fentanyl was administered into the epidural space as a bolus (0.03 mg followed by 0.1 mg 210 min later) and as an infusion (0.03 mg/h followed by 0.1 mg/hr 210 min later for 200 min). Using a thermal and electrical experimental pain model, the heat ( degrees C) and electrical current (mA) causing maximum tolerable pain were assessed repetitively over a period of 420 min. The analgesic efficacy measures were obtained at a lumbar and a cranial dermatome. Plasma fentanyl concentrations were determined throughout the study. Epidural bolus administration of fentanyl resulted in segmental analgesia (leg > head), whereas the epidural infusion of fentanyl produced nonsegmental analgesia (leg = head). There was a significant linear relationship between the analgesic effect and the plasma concentration of fentanyl for the epidural infusion but not for the epidural bolus administration of fentanyl. These findings support our hypothesis and might explain the apparent conflict in the literature regarding the site of action of epidural fentanyl. IMPLICATIONS: In an experimental pain study in volunteers, epidural fentanyl caused segmental analgesia when administered as a bolus and nonsegmental systemic analgesia when administered as a continuous infusion. This finding may help resolve the long-standing controversy surrounding the site of action of epidural fentanyl.

Adult↗
PubMed1987

Long term intrathecal administration of morphine: a comparison of bolus injection via reservoir with continuous infusion by implanted pump.

Twenty-six cases of chronic intrathecal morphine administration are described: 19 cases utilizing the Spinalgesic injectable subcutaneous reservoir and 7 cases utilizing the Infusaid implanted infusion pump. In 25 cases, the morphine was delivered into the spinal subarachnoid space, and in 1 case of thalamic pain it was delivered into the temporal horn of the ipsilateral cerebral ventricle. The average duration of usage of the system was 132 days. The efficacy of the method was excellent: 23 of 26 patients used no other analgesics or only minor ones such as aspirin, paracetamol, or dextropropoxyphene. The complication rate was low, with no infections under the author's care, and only 4 catheter blockages (1 by tumor). There have been no complications in the 7 patients with implanted pumps. From this experience, the author concludes that the implanted pump is now the method of choice in all patients who can afford it and for whom the life expectancy outside an institution is in excess of 60 days. A special and relatively absolute indication for the pump is the situation of pain in the arm, head, or neck areas, in which case the constant morphine levels likely to be achieved with the pump may prevent failure of the method due to intractable nausea or emesis. The subcutaneous reservoir is otherwise to be preferred if the patient's disease is progressing rapidly, if the patient is already institutionalized and likely to remain so, or where the cost of the implanted pump would cause hardship. Either method of delivery of morphine to the subarachnoid space can provide incomparable analgesia without clouding of consciousness, with a very low complication rate.

Adult↗
PubMed1994

Glycine and GABAA antagonists reduce the inhibition of primate spinothalamic tract neurons produced by stimulation in periaqueductal gray.

Amino acids are demonstrated to be important neurotransmitters mediating the inhibitory transmission from nucleus raphe magnus to spinal nociceptive dorsal horn neurons. In this study, the role of glycine and GABA in the inhibitory processes evoked by stimulation in periaqueductal gray (PAG) of responses of primate spinothalamic tract (STT) neurons to cutaneous mechanical and thermal stimuli was investigated by examining the effects of strychnine and bicuculline, antagonists of glycine and GABAA receptors, respectively, introduced into the dorsal horn through a microdialysis fiber. The inhibitory effects of iontophoretic application of glycine and GABAA agonists on STT cell activity evoked by noxious mechanical stimulation of the skin were selectively blocked by their specific antagonist, strychnine or bicuculline, infused into the dorsal horn. Similarly, intra-spinal application of strychnine or bicuculline resulted in a significant reduction in the PAG stimulation-induced inhibition of responses of STT cells to cutaneous stimuli. This reduction was mainly on the PAG-induced inhibition of the responses to noxious mechanical stimuli. Our results suggest that glycinergic and GABAergic inhibitory interneurons in the spinal cord dorsal horn synapsing on STT cells are activated during stimulation in PAG and contribute to descending antinociceptive actions.

Animals↗
PubMed1993

Chronic pain in the spinal cord injured: statistical approach and pharmacological treatment.

We include in this article the results of a postal inquiry into chronic pain in SCI patients in Valencia (Spain), and our experience with their management. A mailed questionnaire including lesion and chronic pain data was sent to all of the 380 SCI patients who live in the region of Valencia. We received 202 answers, with 145 questionnaires being accurately answered and these were analysed for this study. The results show that chronic pain (that is, lasting more than 6 months) is very common (65.5%). The most frequent type was deafferentation pain (phantom pain), described as burning or a painful numbness. Since 1988 we have been treating a sample of 33 patients suffering from resistant pain according to the following therapies: 1 amitriptyline + clonazepam+NSAID (nonsteroidal antiinflammatory drugs); 2 amitriptyline + clonazepam + 5-OH-tryptophane + TENS (transcutaneous electrical nerve stimulation); 3 amitriptyline + clonazepam + SCS (spinal cord stimulation); 4 morphine, by continuous intrathecal infusion. After almost 4 years using these therapies we can affirm that the results regarding analgesia reached 80% in all cases, and that morphine used by intrathecal route is very safe and useful in selected patients.

Adolescent↗
PubMed2003

Effects of chronic intrathecal infusion of a partial differential opioid agonist in dogs.

To define the effects of chronic spinal exposure to a highly selective partial differential opioid agonist c[DPen(2),DPen(5)]enkephalin (DPDPE), adult beagles were prepared with chronic lumbar intrathecal catheters. Groups of dogs received intrathecal infusions (100 micro l/h) of saline (vehicle), DPDPE 3 mg/ml or 6 mg/ml for 28 days. Over the 28-day period, saline or 3 mg/ml showed minimal changes in neurological function, whereas in the 6 mg/ml animals, prominent hind limb dysfunction evolved over the 28-day interval. Histopathology in control animals displayed a modest pericatheter reaction considered normal for this model. Dogs receiving DPDPE (three of four at 6 mg/ml and one of four at 3 mg/ml) but not saline (zero of four) developed large inflammatory masses (granulomas) in the intrathecal space located proximal to the catheter tip. In these masses, severe chronic inflammatory changes in combination with necrosis and fibrosis was detected. Occasional focal destruction of neuropil was detected also in the adjacent spinal cord parenchyma. These masses contained extensive accumulation of mouse antihuman macrophages (MAC)-positive inflammatory cells expressing tumor necrosis factor-alpha (TNF-alpha), revealing infiltration of macrophages, granulocytes, and monocytes. In separate animals, prepared with dual intrathecal catheters, lumbar CSF was sampled at specified time points following intrathecal bolus (3 mg/ml) and 24 h DPDPE infusion (3 mg/ml and 6 mg/ml). Steady-state cerebrospinal fluid (CSF) DPDPE levels were 18.6 +/- 1.0 and 22.6 +/- 4.0 micro g/ml for 3 mg/ml and 6 mg/ml infusions respectively. These results indicate that this partial differential opioid agonist DPDPE produces a concentration and time-dependent formation of an intrathecal inflammatory mass.

Analgesics, Opioid↗
PubMed2005

Physiological and behavioral evidence for focal nociception induced by epidural glutamate infusion in rats.

STUDY DESIGN: Blinded animal study. OBJECTIVES: To determine if an increased concentration of epidural glutamate can cause a focal nociceptive response in the lower extremities that is consistent with sciatica. SUMMARY OF BACKGROUND DATA: It is believed that the origin of sciatic pain is related to more than physical pressure on the nerve roots. Recently, it was determined that disc material may be a significant source of free glutamate, resulting from the enzymatic degradation of matrix aggrecan proteins. We believe that this free glutamate acts as a neurotransmitter at glutamate receptors on the dorsal root ganglion (DRG) cell bodies, thereby initiating a nociceptive response. METHODS: Rats were subject to a 72-hour epidural glutamate infusion via a mini osmotic pump. Von Frey behavioral testing was performed 24 hours before, and 24 and 72 hours after the onset of the infusion. DRG and dorsal horn tissues were analyzed for changes in receptor expression, which have been previously shown to correlate with a nociceptive state. RESULTS: Von Frey behavioral tests showed focal hyperalgesia that was maximal at the 0.02 mmol/L glutamate concentration. Significant changes in DRG glutamate receptor expression were seen for alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid, kainite, and N-methyl-D aspartate receptors. Analysis of dorsal horn glutamate receptors also showed patterns in alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid and kainate receptor expression that were consistent with a nociceptive state. CONCLUSIONS: Epidural glutamate elicits a focal nociceptive response. Free glutamate that has been liberated from the disc material may be an important factor in the development of sciatic pain.

Animals↗
PubMed1994

[Treatment of cancer pain with continuous opioid via spinal catheters].

Continuous intrathecal morphine treatment of cancer pain is reviewed on the basis of a literature search. Clinical, pharmacological and technical aspects are described, and the indications and potential complications are discussed. Three case histories illustrate the practical conduct and problems. The authors conclude that continuous intrathecal morphine treatment offers significant therapeutical advantages, when pain relief is not provided by conventional methods.

Analgesia, Patient-Controlled↗
PubMed1988

Effects of volume loading on paraventriculo-spinal neurones in the rat.

Experiments were carried out to investigate the effects of volume loading on the activity of antidromically identified paraventriculo-spinal neurones in rats anaesthetised with urethane. Intravenous infusion of isotonic saline (1.5-4.2 ml) inhibited amino acid induced activity in 12/20 cells. Of the remainder, 4 cells were excited and 4 were unaffected by volume loading. In 4/4 neurones inhibited by volume expansion, subsequent activation of vagal afferent nerve endings by i.v. bolus injection of 5-hydroxytryptamine (25-100 micrograms) also inhibited cell firing. The onset (0.5-7 min) and duration (5-29 min) of the inhibition evoked by volume loading showed considerable variation in different animals. The inhibitory effects of volume loading were absent in bilaterally vagotomised rats (n = 4). In these preparations the activity of paraventriculo-spinal neurones was facilitated by volume loading. It is suggested that during volume loading inhibitory vagally mediated inputs and excitatory non-vagal influences converge on paraventriculo-spinal neurones.

Afferent Pathways↗
PubMed1996

Intrathecal clonidine and baclofen in the management of spasticity and neuropathic pain following spinal cord injury: a case study.

Spasticity and pain are common disabling sequelae following spinal cord injury (SCI) and are often difficult to manage. The two problems are also not infrequently related. A variety of pharmacological and other approaches have been described for management of these problems in SCI. This case study reports a 32-year-old woman with an established incomplete C5 tetraplegia (anterior cord syndrome) who developed severe, intractable anal spasm following a hemorrhoidectomy, which persisted despite very good healing. This prevented evacuation of her bowels and resulted in severe rectal pain and episodes of autonomic dysreflexia. Attempts to modify the rate and mode of delivery of intrathecal baclofen through an existing programmable infusion pump failed to reduce anal sphincter spasm or improve symptoms. A right-sided pudendal block with lignocaine provided some relief. Clonidine was added to baclofen in the pump reservoir and both drugs were administered intrathecally in combination. This resulted in an immediate improvement in anal sphincter spasm and pain relief, allowing rapid reestablishment of her normal bowel pattern without need for any supplemental analgesia. It appears that intrathecal clonidine may have an important role in the treatment of spasticity, either as a single or an adjuvant agent, when intrathecal baclofen alone is ineffective or there is increasing tolerance to baclofen. Intrathecal clonidine may also prove useful in the management of intractable neuropathic pain.

Adult↗