Mu, Delta and Kappa Opioid Agonist Effects In Novel Assays of Pain

Chapter 9

Mu, Delta and Kappa Opioid Agonist Effects In Novel Assays of Pain-Depressed Behavior Downloaded by UNIV ILLINOIS URBANA on May 14, 2013 | http://pubs.acs.org Publication Date (Web): May 10, 2013 | doi: 10.1021/bk-2013-1131.ch009

S. Stevens Negus* and Ahmad A. Altarifi Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th Street, Richmond, Virginia 23298 *[email protected]

Pain is associated with stimulation of some behaviors (e.g. reflexive withdrawal responses) but depression of many other behaviors (e.g. feeding, locomotion, positively reinforced operant responding). This chapter reviews effects of mu, delta and kappa opioid agonists in novel assays of pain-depressed behavior, with a particular focus on studies in which intraperitoneal injection of dilute acid served as a noxious stimulus to depress the positively reinforced operant behavior of intracranial self-stimulation (ICSS). Mu agonists such as morphine reliably block most forms of pain-depressed behavior, including acid-induced depression of ICSS. Although delta agonists have not been extensively studied in assays of pain-depressed behavior, the delta agonist SNC80 also blocked acid-induced depression of ICSS. Kappa agonists fail to produce antinociception in assays of pain-depressed behavior, and centrally penetrating kappa agonist such as salvinorin A and U69,593 exacerbate pain-related behavioral depression. The efficacy of mu but not kappa agonists to block pain-related depression of behavior agrees with the clinical finding that mu but not kappa agonists function as effective analgesics in humans. These results suggest that novel assays of pain-depressed behavior may improve predictive validity of preclinical research on development of opioids and other drugs as candidate analgesics.

© 2013 American Chemical Society In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Downloaded by UNIV ILLINOIS URBANA on May 14, 2013 | http://pubs.acs.org Publication Date (Web): May 10, 2013 | doi: 10.1021/bk-2013-1131.ch009

Introduction Preclinical assays of animal behavior have played a key role in research on the neurobiology of pain and development of analgesic drugs (1). These preclinical assays share two common elements: (a) a set of independent variables implemented with the intent of producing a pain state, and (b) a dependent measure of behavior interpreted as evidence of that pain state. As one simple example, tail-withdrawal assays of thermal nociception apply a noxious thermal stimulus (e.g. a hot light or hot water) to the tail of a rodent or non-human primate and measure the latency to a tail withdrawal response. In this example, application of the hot stimulus is intended to produce “pain,” and tail withdrawal is an unconditioned behavioral response interpreted as evidence of “pain.” Drugs or other treatments can then be evaluated for their effects on expression of the pain-related behavior. This simple type of assay has proven especially useful for studies of pharmacology (e.g. for determination of potency, efficacy, time course and receptor mediation of opioid effects); however, results often fail to translate to human studies of pain and analgesia (1–5). Shaped in part by efforts to increase the relevance and predictive validity of preclinical research for clinical treatment of pain in humans, these simple assays have evolved in two general ways (1). First, with regard to the independent variables, methods have been developed to model inflammatory or neuropathic states that render subjects more sensitive to provocative mechanical or thermal stimuli. Second, with regard to dependent measures, new assays have been developed to assess new classes of pain-related behaviors. This chapter will focus on opioid effects in the latter type of assay. Many pain-related behaviors can be assigned to two general categories that we have called “pain-stimulated behaviors” and “pain-depressed behaviors” (6). Pain-stimulated behavior can be defined as any behavior that increases in rate, frequency or intensity after presentation of a noxious stimulus, and common examples include withdrawal responses from escapable stimuli (such as tail-withdrawal responses from thermal stimuli as described above) or pseudowithdrawal responses from inescapable stimuli (e.g. stretching or flinching responses elicited by injection of noxious chemical stimuli). Antinociception in assays of pain-stimulated behavior are indicated by drug-induced decreases in the target behavior. For example, Figure 1 shows effects of a mu opioid agonist (morphine), delta agonist (SNC80) and kappa agonist (salvinorin A) in an assay of acid-stimulated stretching in rats (7–9). In this assay, intraperitoneal injection of dilute lactic acid served as chemical noxious stimulus to elicit a repetitive stretching response, and the number of stretches was counted during a 30 min observation period. All three opioids produced a dose-dependent decrease in acid-stimulated stretching, and these effects were blocked by selective mu, delta or kappa antagonists (data not shown). The antinociceptive effects observed in this assay are similar to antinociceptive effects of mu, delta and kappa opioid agonists in many other assays of pain-stimulated behavior, and such data have often been interpreted as evidence of analgesic effects of mu, delta and kappa agonists. However, exclusive reliance on pain-stimulated behaviors to evaluate effects of opioids or other candidate analgesics is problematic for several reasons (1). Perhaps most importantly, drug-induced decreases in pain-stimulated 164 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


behavior can be produced not only by a selective reduction in sensory sensitivity to the noxious stimulus (i.e. true analgesia) but also by nonselective effects such as motor impairment (resulting in “false positive” effects). Notably, kappa agonists have failed to produce safe and/or effective analgesia in human studies despite their frequently observed efficacy in preclinical assays of pain-stimulated behavior.

Figure 1. Opioid antinociception in an assay of acid-stimulated stretching. Abscissae: Dose in mg/kg, log scale. Ordinates: Percent vehicle control number of stretches observed during the 30 min after intraperitoneal injection of dilute acid (1.8% lactic acid in a volume of 1.0 ml/kg). Each bar shows mean+SEM from 5-6 rats. Asterisks indicate significantly different from “0” dose for each drug. Baseline rates of stretching were 14.0±3.0 for morphine, 18.2±1.9 for SNC80 and 28.4±4.2 for salvinorin A. Data for morphine are unpublished (Altarifi and Negus); data for SNC80 and salvinorin A are adapted from (8, 9).

By contrast to pain-stimulated behaviors, pain-depressed behaviors can be defined as behaviors that decrease in rate, frequency or intensity after presentation of a noxious stimulus, and common examples include pain-related decreases in feeding, locomotor activity, or rates of positively reinforced operant responding (6). Importantly, antinociception in assays of pain-depressed behavior is indicated by an increase in the target behavior, and as a result, these assays are not vulnerable to false-positive effects of drugs that produce motor impairment. Assays of pain-depressed behavior may also add value in analgesic drug development for two other reasons. First, the diagnosis of pain in both human and veterinary medicine often relies on measures of pain-depressed behavior (also referred to as “functional impairment”), and restoration of pain depressed behavior is often a goal of treatment (10–13). The utility of these measures in clinical contexts suggests that pain-depressed behaviors may also be useful as endpoints in research. Second, pain-related depression of behavior is often accompanied by comorbid depression of mood in humans (14, 15), and preclinical research on pain-depressed behavior may provide insights into the expression, neurobiology and modulation of the affective dimensions of pain. 165 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Figure 2. Intraperitoneal acid depresses ICSS. Panel a shows acid effects on ICSS frequency-rate curves. Abscissa: frequency of brain stimulation in Hz, log scale. Ordinate: rate of ICSS expressed as percent maximum control rate (%MCR, a normalized measure of ICSS rate, see references for further details). Number sign (#) indicates frequencies at which ICSS was lower after acid than after saline treatment as determined by two-way ANOVA followed by a Holm-Sidak post hoc test. Panel b shows the same data in summary form. Abscissa: treatment with lactic acid vehicle (LA Veh) or 1.8% lactic acid (1.8% LA). Ordinate: percentage of baseline number of stimulations per component. Number sign (#) indicates significantly different from LA Veh as determined by paired t-test. All data show mean±SEM from 34 rats. Data adapted from (8). Assays of pain-depressed behavior can measure pain-related decreases in any of a variety of behaviors, although to be experimentally useful, baseline rates of the target behavior should be relatively high (to permit detection of pain-related decreases), stable (to permit differentiation of effects produced by noxious stimuli and/or drugs from natural variability), and quantifiable (to permit precise and objective measurement) (6). Operant conditioning provides one strategy for generating high, stable and quantifiable rates of baseline behavior that can be used to assess effects of drugs or other manipulations, and Figure 2 shows an example of operant behavior that can be depressed by a noxious stimulus (8). In this assay of intracranial self-stimulation (ICSS), rats were implanted with intracranial electrodes targeting the medial forebrain bundle, and lever-press responding was maintained under a fixed-ratio 1 schedule of brain stimulation. The ability of brain stimulation to function as a reinforcing stimulus was discovered more than 50 years ago (16), and ICSS maintained by stimulation of the medial forebrain bundle is mediated by activation of excitatory inputs to mesolimbic dopamine neurons that originate in the ventral tegmental area (17, 18). In the procedure used here, daily sessions consisted of multiple components, and the magnitude of the brain stimulation reinforcer was manipulated across components by manipulating the frequency of stimulation in a descending series of 10 steps from 158 Hz to 56 Hz in 0.05 log unit increments. On test days, response rates maintained across this range of frequencies was evaluated before (baseline) and 166 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


after intraperitoneal administration of either vehicle (water) or a chemical noxious stimulus (dilute lactic acid, the same noxious stimulus used above for studies of acid-stimulated stretching). The left panel of figure 2 (Fig. 2a) shows that, under baseline conditions, increasing frequencies of brain stimulation maintained increasing rates of ICSS, and as with many types of operant responding, these frequency-dependent rates of ICSS can be maintained at stable levels for months. Treatment with acid vehicle had no effect on the ICSS frequency-rate curve, but treatment with the dilute acid noxious stimulus depressed ICSS at frequencies of 79 Hz and higher. The right panel of figure 2 (Fig. 2b) summarizes this finding by showing the total number of stimulations across all frequencies as a percent of the baseline number of stimulations across all frequencies, and acid significantly decreased this measure of total ICSS. Overall, then, acid-induced depression of ICSS provides one example of pain- depressed behavior, and analgesics would be expected to block acid-induced depression of ICSS.

Effects of Mu Agonists on Pain-Depressed Behavior The mu agonist morphine dose-dependently blocks acid-induced depression of ICSS (7, 19). Figure 3 shows the effect of one experiment with a dose of 1.0 mg/kg morphine. The left panel (Fig. 3a) compares the effects of morphine or its vehicle in the absence of the noxious stimulus (lactic acid vehicle), and this dose of morphine had no effect on the ICSS frequency-rate curve under these conditions. The center panel (Fig. 3b) compares the effects of morphine and its vehicle administered as pretreatment to the acid noxious stimulus. After morphine vehicle, acid depressed ICSS as described above and produced a rightward shift in the ICSS frequency-rate curve (compare open diamonds in 3a and closed diamonds in 3b). Pretreatment with morphine blocked this acid-induced depression of ICSS and prevented the acid-induced rightward shift in the ICSS frequency-rate curve. The right panel (Fig. 3c) shows in summary form that 1.0 mg/kg morphine had no effect on ICSS in the absence of the noxious stimulus but blocked acid-induced depression of ICSS. Three additional points related to this experiment warrant mention. First, acid-induced depression of ICSS is also dose-dependently blocked by other mu agonist analgesics including methadone, hydrocodone and buprenorphine (20). Second, as shown in Table 1, morphine has been shown to block many other examples of pain-depressed behavior produced by several other types of pain manipulation. Together, these findings suggest considerable generality in the ability of mu agonists to block pain-related depression of behavior. Finally, the study shown in Figure 3 illustrates the value of including control experiments that examine effects of test drugs administered alone in the absence of noxious stimulation. In this case, the test dose of morphine did not alter ICSS when administered alone, suggesting that morphine effects on acid-depressed ICSS could be more confidently attributed to antinociception and not to nonselective effects of morphine on the target behavior. However, mu agonists and other test drugs often do affect expression of the target behavior, and these effects in the absence of pain can assist with interpretation of drug effects in the presence 167 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


of pain. As one example, the effects of morphine in Table 1 were often shown to display an inverted U-shaped dose-effect curve with peak antinociception at intermediate morphine doses. In these studies, high morphine doses typically depressed the target behavior in the absence of stimulation and produced little or no blockade of pain-induced depression of behavior. Such findings are often interpreted as evidence that sedative effects of high mu agonist doses may obscure expression of antinociception in assays of pain-depressed behavior, in which antinociception is manifested as an increase in rates of the target behavior.

Figure 3. Morphine blocks acid-induced depression of ICSS. Panels a and b show morphine effects on ICSS frequency-rate curves in the absence (a) or presence (b) of the noxious acid stimulus. Abscissae: frequency in Hz, log scale. Ordinates: rate of ICSS expressed as percent maximum control rate (%MCR). Asterisk (*) indicates frequencies at which ICSS was higher after morphine+acid than after vehicle+acid as determined by two-way ANOVA followed by a Holm-Sidak post hoc test. Panel c shows the same data in summary form. Abscissa: morphine dose in mg/kg. Ordinate: percentage of baseline number of stimulations per component. Number sign (#) indicates a significant depression of ICSS by acid; asterisk (*) indicates that morphine blocked acid-induced depression of ICSS. All data show mean±SEM from 6 rats. Unpublished data from Altarifi and Negus with procedures as in (7, 16). Although data on “sedative” effects can identify drug doses at which antinociception might be obscured, it is also important to consider the degree to which a test drug might produce nonselective increases in the target behavior, because nonselective behavioral stimulation can produce false-positive effects in assays of pain-depressed behavior (6). Assessment of drug-induced increases in behavior can be difficult with many endpoints, such as feeding, locomotion or food-maintained operant responding under fixed-ratio schedules, because the target behavior occurs at a relatively high and constant rate in the absence of pain, and further increases may be difficult to produce or detect. This issue can be addressed by incorporating conditions that generate both low and high rates of baseline behavior, and ICSS is ideal for this purpose. The magnitude of the brain-stimulation reinforcer can be rapidly manipulated across a range of values to engender a range of baseline behavioral rates such as those shown in Figures 2 and 3. Consequently, drug effects on low rates of pain-depressed ICSS can be compared to drug effects on low rates of behavior maintained by low reinforcer 168 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


magnitudes in the absence of pain. As discussed above with Figure 3, 1.0 mg/kg morphine blocked acid-induced depression of ICSS without increasing low rates of baseline ICSS in the absence of pain, and this finding suggests that morphine effects on acid-depressed ICSS reflect a true blockade of sensory sensitivity to the acid stimulus rather than a nonselective behavioral stimulation. It is important to note that morphine and other mu agonists can facilitate ICSS under other conditions (21–25), but this experiment illustrates the potential for mu agonists to selectively block pain-related depression of behavior. Moreover, these results with morphine contrast with effects of cocaine in the same procedure. Cocaine also blocked acid-induced depression of ICSS, but only at doses that also produced robust facilitation of ICSS in the absence of pain (8).

Effects of Delta Agonists on Pain-Depressed Behavior Figure 4 shows that the delta agonist SNC80 also dose-dependently blocked acid-induced depression of ICSS at doses that had no effect on control ICSS in the absence of the noxious stimulus (9). Taken together with the efficacy of SNC80 to block acid-stimulated stretching (Figure 1), these results support further consideration of delta agonists as candidate analgesics. However, in contrast with morphine, SNC80 effects on acid-depressed ICSS were determined in part by regimens of repeated dosing. Upon initial administration, or when SNC80 doses were separated by weekly intervals, low doses of SNC80 (e.g. 1.0 mg/kg) only weakly attenuated acid-induced depression of ICSS, and higher doses (e.g. 10 mg/kg) depressed ICSS in the absence of the acid noxious stimulus and failed to block acid-induced depression of ICSS. However, when SNC80 was administered more frequently (e.g. twice per week as shown in Figure 4), higher doses of SNC80 no longer depressed control ICSS, and a full antinociceptive blockade of acid-induced depression of ICSS was observed. These results were interpreted to suggest that initial or intermittent SNC80 produced sedative effects that obscured expression of antinociception in the assay of pain-depressed behavior; however, more frequent injections produced tolerance to sedative effects and unmasked expression of antinociceptive effects. Moreover, dosing regimens that increased expression of antinociception in the assay of acid-depressed ICSS also decreased expression of antinociception in the assay of acid-stimulated stretching (i.e. SNC80 dosing at short intervals reduced the ability of SNC80 to decrease acid-stimulated stretching). These findings were interpreted to have two implications. First, they suggested that SNC80-induced sedation contributed to apparent antinociception in the assay of acid-stimulated stretching but opposed antinociception in the assay of acid-depressed ICSS. Second, they provide evidence for differential modulation of drug effects in assays of pain-stimulated and pain-depressed behaviors, even when the putative pain state has been produced with the same noxious stimulus (in this case, intraperitoneal acid injection) (9). With SNC80, apparent antinociceptive tolerance in the assay of acid-stimulated stretching was accompanied by enhanced expression of antinociception in the assay of acid-depressed ICSS. 169 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Table 1. Morphine effects in preclinical assays of pain-depressed behavior. Pain Manipulation

Behavioral Endpoint

Morphine Effective

Ref.

Mouse

Intraperitoneal Acetic Acid

Feeding

Yes

(36)

Mouse


Locomotion

Yes

(37)

Mouse


Wheel Running

Yesa

(38)

Feeding

No


Species

a

Mouse

Intraplantar Complete Freunds Adjuvant (CFA)

Wheel Running

Yesa

(39)

Rat

Laparotomy

Locomotion, Food-Maintained Operant Responding

Yesa

(40)

Rearing

No

Rat

Facial Carrageenan +Heat

Food-Maintained Operant Responding

Yes

(41)

Rat

Facial Capsaicin +Heat

Food-Maintained Operant Responding

Yes

(42)

Rat


Rearing

Partial

(26)

Rat

Intra-articular CFA

Rearing

Yesa

(43)

Rat


Intracranial Self-Stimulation

Yesa

(7)

Dog

Intra-articular Formalin

Locomotion

Yes

(44)

Indicates inverted-U shaped morphine dose-effect curve.

In addition to these studies with SNC80, the other putative delta agonist ARM390 was also tested in assays of acid-stimulated stretching and acid-depressed ICSS (9). ARM390 is a congener of SNC80 reported to produce delta receptor-mediated antinociception in assays of pain-stimulated behavior in mice but with a lower propensity than SNC80 to internalize delta receptors or produce acute antinociceptive tolerance. However, in contrast to these results in mice, ARM390 failed to produce antinociception in rats in assays of either acid-stimulated stretching or acid-depressed ICSS. 170 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Figure 4. Blockade of acid-induced depression of ICSS by the delta agonist SNC80 but not by the kappa agonist salvinorin A. Abscissae: Dose SNC80 (left panel) or salvinorin A (right panel) in mg/kg. Ordinates. Percentage of baseline number of stimulations per component. Drug effects in the absence or presence of the noxious stimulus are shown by open and filled bars, respectively. Number signs (#) indicates a significant depression of ICSS by acid; asterisks (*) indicate significant effect of test drug on ICSS relative to the "0" dose in the absence or presence of the acid noxious stimulus. Each drug was tested in a group of 6 rats. Data adapted from (8, 9).

Effects of Kappa Agonists on Pain-Depressed Behavior Kappa opioid receptor agonists do not produce antinociception in the assay of acid-depressed ICSS (8, 19). Figure 4 shows results from one experiment with the kappa agonist salvinorin A, which is an active constituent from the plant salvia divinorum. As has been shown previously with salvinorin A and other kappa agonists, salvinorin A in this study produced a dose-dependent decrease in control ICSS in the absence of noxious stimulation. Low salvinorin A doses that did not affect control ICSS also failed to block acid-induced depression of ICSS, and higher salvinorin A doses that decreased control ICSS also exacerbated acid-induced depression of ICSS. Similar results have been obtained with the other selective and high-efficacy kappa agonist U69,593 in the assay of acid-depressed ICSS. Moreover, the kappa-2 opioid receptor agonist GR89,696 failed to block pain-related depression of rearing and food-maintained operant responding in rats (26). These findings are notable for two general reasons. First, results with these kappa agonists illustrate the potential for a complete dissociation of drug effects in assays of pain-stimulated and pain-depressed behavior. For example, salvinorin A produced antinociception at doses of 1.0 and 3.2 mg/kg in the assay of acid-stimulated stretching in rats (see figure 1), but these same doses of salvinorin A decreased control ICSS and exacerbated pain-related depression of ICSS in the assay of acid-depressed ICSS. Taken together, these results suggest that salvinorin A and other kappa agonists do not produce analgesia, but rather produce nonselective behavioral depression that manifests as “false-positive” 171 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


antinociception in assays of pain-stimulated behavior. Second, the failure of kappa agonists to produce antinociception in assays of pain-depressed behavior agrees with the failure of kappa agonists to produce safe and/or effective analgesia in humans (27–29). This provides one source of evidence to suggest that preclinical assays of pain-depressed behavior may have greater predictive validity than assays of pain-stimulated behavior for forecasting analgesic effects of test drugs in humans. One strategy for improving the safety of kappa agonists has been to develop compounds that do not readily cross the blood-brain barrier and hence remain peripherally restricted after systemic administration (30). This approach is founded on the notion that peripherally restricted kappa agonists might retain an ability to produce antinociception by acting at peripheral kappa receptors while displaying reduced potency to produce undesirable effects mediated by central kappa receptors. Consistent with this hypothesis, the peripherally restricted kappa agonists ffir and ICI204,448 both produced a dose-dependent decrease in acid-stimulated stretching at doses that did not alter control ICSS; however, neither drug blocked acid-induced depression of ICSS (8). By contrast, the nonsteroidal antiinflammatory drug (NSAID) ketoprofen blocked both acid-stimulated stretching and acid-induced depression of ICSS without affecting control ICSS (8). These results were interpreted to suggest that although peripherally restricted kappa agonists may be somewhat safer than centrally penetrating kappa agonists like salvinorin A, they are less efficacious than mu agonists or NSAIDs for blocking pain-related depression of behavior. This conclusion agrees with the poor and inconsistent analgesic efficacy of peripherally restricted kappa agonists studied to date in humans (31–35) and provides another example of concordance between preclinical studies of pain-depressed behavior and human studies of pain and analgesia.

Summary and Conclusions Historically, analgesic drug development has relied almost exclusively on preclinical assays of pain-stimulated behaviors. However, pain states are often associated with depression of behavior, and restoration of pain-related depression is often a goal of treatment. Novel assays of pain-depressed behavior are providing new research tools for evaluating both the expression and treatment of pain-related behavioral depression, and these assays have provided new insights into opioid agonist effects. Consistent with their clinical analgesic efficacy, mu agonists have typically produced antinociception in assays of both pain-stimulated and pain-depressed behavior. The delta agonist SNC80 also produced antinociception in both types of assays, although regimens of repeated treatment produced opposite effects on SNC80 antinociception in assays of pain-stimulated behavior (tolerance) and pain-depressed behavior (enhancement). Further studies with other delta agonists are warranted. Kappa agonists have produced antinociception in most assays of pain-stimulated behavior, but in agreement with their poor clinical efficacy, they have failed to produce antinociception in assays of pain-depressed behavior and often exacerbate pain-related behavioral depression. 172 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Table 2. Effects of opioids and other drugs in assays of acid-stimulated stretching and acid-depressed ICSS in rats. Drugs in bold are antinociceptive in both assays. References are shown in the footnotes.


Effective In Assay of Acid-Stimulated Stretching

Not Effective In Assay of Acid-Stimulated Stretching

Effective In Assay of Acid-Depressed ICSS

Methadone1 Fentanyl1 Morphine1 Hydrocodone1 Buprenorphine1 Nalbuphine SNC802 Ketoprofen3

Cocaine4

Not Effective In Assay of Acid-Depressed ICSS

Salvinorin A5 U69,5935 ffir6 ICI204,4486 Δ9-THC7 CP559407 Flupenthixol8

Naltrexone9 Naltrindole10 Norbinaltorphimine11

1

Mu opioid receptor agonist (7, 19, 20) 2 Delta opioid receptor agonist (9). 3 Nonsteroidal antiinflammatory drug (8, 45) 4 Monoamine reuptake inhibitor (dopamine, serotonin, norepinephrine nonselective) (8). 5 Kappa opioid receptor agonist (centrally penetrating) (8, 19) 6 Kappa opioid receptor agonist (peripherally restricted) (8). 7 Cannabinoid-1 receptor agonist (45). 8 Dopamine receptor antagonist (8). 9 Opioid receptor antagonist (unpublished). 10 Delta opioid receptor antagonist (9). 11 Kappa opioid receptor antagonist (19).

We have also examined other drugs from other drug classes in our assays of acid-stimulated stretching and acid-induced depression of ICSS. Results are summarized in Table 2. An important conclusion from this table is that clinically effective analgesics block both acid-stimulated stretching and acid-induced depression of ICSS, whereas drugs effective in only one or the other type of assay are generally not effective clinical analgesics against acute pain. These findings support the utility of assays of pain-depressed behavior as a complement to more conventional assays in the preclinical evaluation of candidate analgesics. Lastly, it should be noted that research with assays of pain-depressed behavior is in its infancy. Future studies will compare the neural substrates of pain-stimulated and pain-depressed behaviors, evaluate the potential for heterogeneity in substrates for pain-related depression of different behaviors, and develop assays for more chronic pain-related depression of behavior.

173 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Acknowledgments This work was supported by R01 NS070715 and R01 DA030404 from the National Institutes of Health. Mr. Altarifi also received support from the Jordan University of Science and Technology.

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