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Anesth Analg 2003;97:168-173
© 2003 International Anesthesia Research Society

PAIN MEDICINE

Peripheral Antihyperalgesic and Analgesic Actions of Ketamine and Amitriptyline in a Model of Mild Thermal Injury in the Rat

Mark Oatway, BSc, Allison Reid, BSc, and Jana Sawynok, PhD

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

Address correspondence and reprint requests to Jana Sawynok, PhD, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7. Address e-mail to jana.sawynok{at}dal.ca


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In this study, we examined antihyperalgesic and analgesic actions after local peripheral administration of ketamine and amitriptyline in a rat model of mild thermal injury. Exposure of the hindpaw to 52°C for 45 s under anesthesia produced a subsequent thermal hyperalgesia lasting at least 2 h. The local peripheral administration of ketamine (100–1000 nmol) 15 min before the thermal injury produced an antihyperalgesic effect when injected into the ipsilateral paw, whereas amitriptyline produced both antihyperalgesic (300 nmol) and analgesic (1000 nmol) effects. Administered after the thermal injury, ketamine had no effect, whereas amitriptyline retained its analgesic but not its antihyperalgesic effect. Amitriptyline (300 and 1000 nmol) produced an analgesic action when administered into the normal nonsensitized hindpaw. Both drugs increase paw volume, particularly at larger doses; biogenic amines are not involved in the action of amitriptyline, as was shown previously for ketamine. These results indicate that (a) ketamine produces antihyperalgesia, but not analgesia, when administered locally with a mild thermal injury model; (b) amitriptyline produces both antihyperalgesia and analgesia when administered locally; and (c) the increase in paw volume produced by these drugs occurs by different mechanisms.

IMPLICATIONS: This study examines the pain-relieving properties of the local peripheral administration of ketamine and amitriptyline, two drugs in current clinical use, in a thermal injury model of hyperalgesia and demonstrates both antihyperalgesic and analgesic properties. These observations provide support for their potential use as local (e.g., topical) analgesics.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Adjuvant analgesics, such as ketamine and amitriptyline, are used in the treatment of chronic and neuropathic pain in humans (1,2). These drugs have traditionally been given systemically (IV and orally, respectively) and likely produce analgesia by recruiting mechanisms within the spinal cord and at supraspinal sites when administered in this manner (3,4,5). Recently, both drugs have been shown to produce peripherally mediated antihyperalgesic and analgesic properties when administered locally in preclinical studies. Thus, peripheral administration of ketamine produces analgesia in the rat formalin test (6; but see Ref. 7), whereas local administration of amitriptyline produces analgesia in the rat formalin test (8) in a neuropathic pain model (9) and in a cutaneous reflex model (10). In clinical reports, topical ketamine was reported to produce analgesia in case studies involving neuropathic and cancer pain (11,12), whereas topical doxepin, another tricyclic antidepressant, produced analgesia in placebo-controlled trials of neuropathic pain (13,14). Although these drugs exhibit promise as potential topical analgesics, the mechanistic basis of their peripheral actions is not well understood.

In humans, a cutaneous thermal injury model has been developed as an investigative paradigm for examining peripheral analgesia. The model generates hyperalgesia to heat and tactile allodynia at the site of injury (primary hyperalgesia and allodynia), as well as tactile allodynia in the undamaged tissue adjacent to the injury (secondary allodynia) (15). With this model, the local peripheral injection of ketamine was shown to produce some antihyperalgesic and analgesic properties in volunteers (16,17). There are, however, no data on the effects of antidepressants in this model in humans.

In the past few years, a model of mild thermal injury has been developed in rats, and this produces both primary thermal hyperalgesia and secondary tactile allodynia (18). This model reveals a local peripheral analgesia with the peripherally acting µ-opioid receptor agonist loperamide (19). In this study, we have used the rat thermal injury model to characterize the potential pain-relieving properties of local peripheral administration of ketamine and amitriptyline. Thermal thresholds were determined in both the paw exposed to the thermal injury (revealing antihyperalgesic and analgesic actions) and the noninjured paw (revealing analgesic actions). In addition, the effects of larger doses of amitriptyline on paw volume were examined. Thus, previous studies had shown that local injection of ketamine into the hindpaw produces a dose-related paw edema (7), whereas amitriptyline at smaller doses produces minimal effects (20). This study was performed to examine the potential for this model to reveal local antihyperalgesic and analgesic properties that might be useful in evaluating the potential of these two drugs to function as peripheral analgesics (e.g., by topical application).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
These studies were performed in accordance with a protocol approved by the University Committee on Laboratory Animals. Male Sprague-Dawley rats (250–300 g) supplied by Charles River (Quebec, Canada) were housed in pairs with free access to food and water and were maintained under standard animal care housing conditions.

Hindpaw thresholds were determined by using a device modeled after that described by Hargreaves et al. (21) (obtained from Department of Anesthesiology, University of California, San Diego, La Jolla, CA). Rats were initially placed in Plexiglas chambers (28 x 28 x 28) on a clear glass surface. This plate was maintained at 30°C to reduce variability in surface temperature due to room temperature fluctuations. A radiant heat source contained in a mobile holder was able to track movements of the rat and, when activated, evoke a hindpaw-withdrawal response to the thermal stimulus. Rats were initially placed in the chambers for 40 min to acclimate to their surroundings. The heat source was positioned to focus on the plantar surface of the hindpaw, which was in contact with the glass, and to avoid footpads. The time from light activation to hindpaw withdrawal was determined electronically. The stimulus was automatically terminated at 20 s to avoid tissue injury. Three baselines were determined before the thermal injury over a 10-min period.

Mild thermal injury was produced as described previously (18). After the determination of baseline latencies, rats were anesthetized with halothane in an induction box and maintained at 2% halothane via a face mask for the duration of the thermal injury. The plantar surface of the hindpaw was placed on a hot plate at 52°C ± 1°C, and constant contact with the surface was maintained by a 10-g sandbag placed on the dorsal surface of the paw for 45 s. This procedure produces a mild erythema, but no blistering, at 24 h (18,19).

Ketamine HCl and amitriptyline HCl (Sigma, St. Louis, MO) were dissolved in saline and administered by intraplantar injection in a volume of 50 µL. Injections entered the plantar surface of the hindpaw near the toe. All treatments were blinded to the investigator performing the thermal threshold determinations.

For pretreatment regimens, rats were acclimated for 40 min, and baselines were determined over a 10-min interval. Injections then were administered into the hindpaw, and rats were anesthetized after 12 min so that the exposure to the hot plate (induction of mild thermal injury) corresponded to 15 min after the injection. Anesthesia was terminated at the end of the 45 s of hot plate exposure, and recovery occurred within 5 min. For the posttreatment regimen, baselines were determined, and the thermal injury was generated as described previously. Injections were made into the hindpaw after the termination of exposure to the hot plate while rats were still anesthetized. In both regimens, postinjury thermal thresholds were then determined at 20, 40, 60, 80, 100, and 120 min after the termination of the thermal injury. Some data are expressed as a cumulative change in paw withdrawal latency, which generates a single indicator representing the area under the time-response curve.

When injections were made into the nonsensitized paw, procedures and time sequences were the same as for the pretreatment regimen, except that rats were not anesthetized and there was no exposure to the hot plate. Paw volume was determined by volume displacement by using a commercially available plethysmometer (Ugo Basile). Determinations were made in triplicate at the beginning of the experiment and then again 30, 60, 90, 120, and 180 min after a 50-µL subcutaneous drug injection into the dorsal hindpaw, the protocol used in previous studies (7,20). Data were analyzed with analysis of variance followed by the Student-Newman-Keuls test and compared either with baseline or with a corresponding saline-pretreated group, as designated in the figure legends.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The application of 52°C heat for 45 s to the rat hindpaw resulted in a significant heat hyperalgesia (Fig. 1). This was most prominent in the first hour after the thermal injury and persisted for up to 2 h. When thermal threshold determinations were made in the contralateral paw, there were minimal alterations in thermal thresholds (Fig. 1).



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  		Figure 1. Effect of mild thermal injury by exposure of the plantar surface of the hindpaw to a 52°C hot plate for 45 s on thermal thresholds as determined by paw withdrawal latency in the sensitized paw or in the contralateral paw. Values are mean ± SEM (n = 8). {dagger}P < 0.05 compared with baseline, which is the mean of three determinations over a 10-min interval.

 
Ketamine, administered locally into the hindpaw at doses of 100–1000 nmol 15 min before the thermal injury, prevented the development of hyperalgesia in response to the thermal injury, whereas a dose of 10 nmol had no effect (Fig. 2). No analgesic effect was observed over this dose range. The 1000-nmol dose injected into the contralateral hindpaw had no effect on hyperalgesia in the paw with the thermal injury (data not shown), indicating that the antihyperalgesia is a local, peripheral action. Amitriptyline 300 nmol injected into the hindpaw as a 15-min pretreatment produced an antihyperalgesic effect, whereas the 1000-nmol dose produced an analgesic effect (Fig. 3). The larger dose injected into the contralateral hindpaw had no effect in the paw with the thermal injury (data not shown), indicating that these effects also were peripherally mediated.



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  		Figure 2. Effect of local peripheral administration of ketamine (KET) on thermal thresholds in the hindpaw after exposure to mild thermal injury depicted as (A) time course and (B) cumulative change in paw withdrawal latency (PWL). Ketamine was injected in 50 µL into the plantar hindpaw 15 min before the thermal injury. Values are mean ± SEM (n = 6–10). {dagger}P < 0.05 compared with baseline; *P < 0.05 compared with the saline-pretreated group.

 


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  		Figure 3. Effect of local peripheral administration of amitriptyline (AMI) on thermal thresholds in the hindpaw after exposure to mild thermal injury depicted as (A) time course and (B) cumulative change in paw withdrawal latency (PWL). Amitriptyline was injected in 50 µL into the plantar hindpaw 15 min before the thermal injury. Values are mean ± SEM (n = 6–8). {dagger}P < 0.05 compared with baseline; *P < 0.05 compared with the saline-pretreated group.

 
Both amitriptyline and ketamine were further administered as a posttreatment immediately after the thermal injury. Amitriptyline at 1000 nmol, but not 300 nmol, produced analgesia in the sensitized paw, but ketamine at 1000 nmol had no such effect (Fig. 4).



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  		Figure 4. Effect of posttreatment injection of amitriptyline (AMI) and ketamine (KET) on thermal thresholds after mild thermal injury. Values are mean ± SEM (n = 6). *P < 0.05 compared with the saline (SAL)-pretreated group.

 
The local effects of pretreatment with amitriptyline on thermal thresholds were further examined in the nonsensitized paw (i.e., no thermal injury). Both the 300- and 1000-nmol doses of amitriptyline injected into a normal paw produced an analgesic action (Fig. 5). In both cases, the extent of this was underestimated because of the imposition of cutoff values; the larger dose produced a longer-lasting action. An intraperitoneal injection of 2 mg/kg, the dose that would result if the 1000-nmol local dose of amitriptyline were redistributed systemically, had no effect on thermal thresholds (data not shown). Injection of 1000 nmol of ketamine into the hindpaw also had no significant effect on thermal thresholds in the nonsensitized paw (Fig. 5).



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  		Figure 5. Effect of intraplantar injection of amitriptyline (AMI) or ketamine (KET) on thermal thresholds in the nonsensitized normal hindpaw. Drugs were injected as a 15-min pretreatment. Values are mean ± SEM (n = 6). *P < 0.05 compared with the saline (SAL)-pretreated group.

 
Ketamine has previously been shown to produce a dose-related edema when injected into the nonsensitized rat hindpaw (7), whereas smaller doses of amitriptyline produce minimal effects on paw volume (20). This study examined the effect of the 1000-nmol dose of amitriptyline on paw volume, because this had not previously been evaluated. Over a 2-h interval, which is the time over which antihyperalgesic and analgesic effects were determined, amitriptyline 1000 nmol produced a similar degree of edema compared with the same dose of ketamine (Fig. 6A, inset). The effect of amitriptyline was not altered by the coadministration of mepyramine (histamine H1 receptor antagonist), phentolamine ({alpha}1- and {alpha}2-adrenergic receptor antagonist), and methysergide (5-hydroxytryptamine [5-HT]1 and 5-HT2 receptor antagonist) (Fig. 6A) at doses that completely inhibited paw edema by ketamine (7). When examined over a longer time interval, the edema produced by amitriptyline exhibited a longer-lasting time course than that produced by ketamine (Fig. 6B).



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  		Figure 6. A, Comparison of the effect of ketamine (KET) and amitriptyline (AMI) on paw volume when injected into the hindpaw of the rat. Paw volumes were determined at 30-min intervals for 2 h after injection and are depicted as an area under the curve in the inset and as a time course in the body of the panel. Hollow symbols depict paw volume in the presence of the biogenic amine receptor antagonists mepyramine (MEP), methysergide (MSG), and phentolamine (PTA). *P < 0.05 compared with saline (SAL) (n = 6). B, Extended time course of the increase in paw volume produced by amitriptyline and ketamine 1000 nmol (n = 5). Data in inset for ketamine (all doses) and amitriptyline (100 and 300 nmol) are redrawn from Refs. 7 and 20, respectively.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, mild thermal injury produced a primary thermal hyperalgesia in the ipsilateral hindpaw of the rat. This was most prominent in the first hour after the injury, persisted in the second hour, and exhibited a similar time course to that observed previously, which indicated recovery to baseline values, by the third hour (19,22). Hyperalgesia may result from nociceptor sensitization because of tissue damage and inflammation produced by thermal exposure with a subsequent release of local tissue inflammatory mediators (23,24), an enhanced sensitivity of Na+ currents in sensory afferents induced by inflammatory mediators (25), and a recruitment of normally silent primary afferents (26). Thermal hyperalgesia in this model can be modulated by a peripherally acting µ-opioid receptor agonist (19), which acts on capsaicin-sensitive afferents (27), and this suggests that hyperalgesia involves capsaicin-sensitive afferents. Thermal injury produced no significant effects in the contralateral hindpaw, although there did appear to be some increase in latency at the first time interval. This may reflect a mild stress-induced analgesia resulting from the procedure.

This study examined the ability of local administration of ketamine and amitriptyline to produce a peripherally mediated antihyperalgesic and/or analgesic response in this model. Ketamine produced an antihyperalgesic but not an analgesic action in the sensitized paw and produced no analgesia in the nonsensitized paw. However, amitriptyline produced both an antihyperalgesic and an analgesic action in the sensitized paw and produced analgesia in the nonsensitized paw. Antihyperalgesic actions of both ketamine and amitriptyline are seen with a pretreatment but not a posttreatment regimen. In contrast, analgesia with amitriptyline is seen with both the pretreatment and posttreatment regimens, and this suggests a dissociation in the mechanisms involved in producing peripheral antihyperalgesia and analgesia.

Both ketamine and amitriptyline share certain cellular mechanisms of action (e.g., block of N-methyl-D-aspartate receptors and local anesthetic actions by blocking Na+ channels), and such mechanisms may contribute to the antihyperalgesia. Increased peripheral release of glutamate, with a subsequent activation of ionotropic and metabotropic glutamate receptors on primary sensory afferents to increase the firing of primary sensory afferents (28–30), has been implicated in inflammatory pain (31). Both ketamine (3) and amitriptyline (32,33) inhibit N-methyl-D-aspartate receptors in neuronal preparations, and this could lead to the antihyperalgesic action. In addition, hyperalgesia involves sensitization of tetrodotoxin-resistant Na+ currents in nociceptors (25), and drugs that block Na+ channels could ameliorate this influence and prevent hyperalgesia. Both ketamine (34,35) and amitriptyline (36,37) have been reported to block neuronal Na+ channels. It is interesting to note that in producing antihyperalgesia with pretreatment, but not posttreatment, regimens, ketamine and amitriptyline resemble the profile of a µ-opioid receptor agonist, which both modulates the effect of an inflammatory mediator on tetrodotoxin-resistant Na+ currents on sensory neurons and produces an antihyperalgesic action only with a pretreatment regimen (38).

Local analgesia in this model was observed only with amitriptyline, was seen after both pre- and posttreatment regimens, and may have involved the recruitment of additional mechanisms. In addition to the effects noted previously, amitriptyline also inhibits noradrenaline, 5-HT, and adenosine uptake; inter-acts with opioid mechanisms; blocks Ca2+ channels; and blocks cholinergic, histamine H1, 5-HT2, and {alpha}-adrenergic receptors. A number of these actions could contribute to peripheral analgesia (39,40). It is important to appreciate that when a drug produces multiple effects, especially at the larger concentrations that can occur after local delivery methods, the overall expression of its effects may reflect actions on more than one of these mechanisms. There is the added potential that some mechanisms may actually interact with others, either enhancing (autoenhancement) or limiting (autoantagonism) actions. For this reason, functional characterization studies are essential in defining the pharmacological properties of drugs that exert multiple pharmacological actions when given by a route of administration that allows for the attainment of larger concentrations than might occur after systemic administration.

In previous studies, we observed that ketamine produced a dose-related paw edema between 30 and 1000 nmol (7). This likely results from inhibition of biogenic amine reuptake, because it is reduced by antagonists for histamine, 5-HT, and adrenergic receptors (7). Although smaller doses of amitriptyline have minimal effects on paw volume (20), this study observed that the 1000-nmol dose produced a significant paw edema. The formation of a wheal after local delivery of large doses of amitriptyline to the dorsal skin of the rat has been noted recently (0.6 mL of 0.05% and 0.5% solutions, equivalent to 900 and 9000 nmol) (10). Paw edema by amitriptyline is not mediated by biogenic amines, because it is not blocked by a range of amine receptor antagonists at doses that completely block the action of ketamine. Thus, although amitriptyline does inhibit biogenic amine reuptake (41), this component of activity may not be expressed because of a simultaneous block of biogenic amine receptors (42) (i.e., autoantagonism occurs). Paw edema by amitriptyline exhibits a longer time course than that produced by ketamine, and the mechanisms underlying the action of amitriptyline remain to be defined.

Paw edema responses appear to be expressed independently of analgesic and antihyperalgesic effects. Thus, although both ketamine and amitriptyline at 1000 nmol produce a similar degree of paw edema, only amitriptyline produced analgesia. Antihyperalgesia and edema appear to coexist, but it is not clear whether the edema modifies the sensory outcome. Thus, edema is generally regarded as a proinflammatory event, yet the doses of ketamine and amitriptyline that produce paw edema reduce rather than augment hyperalgesia. It remains to be determined whether edema also results from topical delivery methods in which there is no injection (and subsequent mechanical effects) into the tissue. Thus, it has been reported that the simple act of injecting saline into the hindpaw causes histamine release from mast cells and some paw swelling as a result of such release (43), and this may be required for expression of this response.

In summary, both ketamine and amitriptyline exhibit local antihyperalgesic properties in a thermal injury model of hyperalgesia, but only amitriptyline exhibits a local analgesia. Such actions appear to be independent of the changes in paw volume produced by these drugs. Given that there are also clinical observations indicating that these drugs can relieve pain by local delivery methods, local peripheral formulations (e.g., by topical delivery) of these drugs may be useful to explore for clinical benefit in the relief of pain.


   Acknowledgments
 
Supported by grants from the Canadian Institutes of Health Research and EpiCept (via Epitome).


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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication March 4, 2003.




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G. H. Zhang, S. S. Min, K. S. Lee, S. K. Back, S. J. Yoon, Y. W. Yoon, Y. I. Kim, H. S. Na, S. K. Hong, and H. C. Han
Intraarticular Pretreatment with Ketamine and Memantine Could Prevent Arthritic Pain: Relevance to the Decrease of Spinal c-Fos Expression in Rats
Anesth. Analg., July 1, 2004; 99(1): 152 - 158.
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C.-P. Yang, C.-C. Yeh, C.-S. Wong, C.-T. Wu, S. Mercadante, P. Villari, P. Ferrera, and E. Arcuri
Local Anesthetic Switching for Intrathecal Tachyphylaxis in Cancer Patients with Pain * Response
Anesth. Analg., February 1, 2004; 98(2): 557 - 558.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press