Effects of cholinergic and dopaminergic agents on pain and morphine analgesia measured by three pain tests

doi:10.1016/0014-4886(83)90166-8

Experimental Neurology

Volume 81, Issue 1, July 1983, Pages 167-176

https://doi.org/10.1016/0014-4886(83)90166-8 Get rights and content

Abstract

The effects of several cholinergic and dopaminergic agents on pain and morphine analgesia were assessed using three pain tests. These tests—tail-flick, hot-plate, and Formalin—allow comparison of the effects of different noxious stimuli and different motor responses. Each pain test yielded a unique constellation of cholinergic and dopaminergic influences, suggesting that variation of stimulus and response parameters can change the functional expression of cholinergic and dopaminergic systems related to pain processing. Significant analgesia was observed in the Formalin test, compared with the saline control, after administration of choline (30 or 60mg/kg), atropine (2 mg/kg), mecamylamine (2 mg/kg or 10 mg/kg), or apomorphine (0.3 or 8 mg/kg). No analgesic effects in this test were observed after atropine (10 mg/kg) or pimozide (0.125 or 0.5 mg/kg). In contrast, there was no evidence of analgesia produced by any of these drugs, in the doses given, in the hot-plate test, and only apomorphine (8 mg/kg) produced analgesia in the tail-flick test. When these cholinergic and dopaminergic agents were administered to rats after an injection of 2.5 mg/kg morphine, which by itself has been shown not to produce analgesia in any of the tests, a general pattern of facilitation was observed in the Formalin test but not in the tail-flick or hot-plate tests. Facilitation was produced by choline, atropine, mecamylamine, apomorphine, and pimozide (at 0.5 mg/kg but not 0.125 mg/kg). The data suggest that differences in the type of noxious stimulation and in the motor responses required in various pain tests are crucial in determining the observed pharmacologic profile of pain and opiate analgesia.

References (25)

S.H.H. Chan
Central neurotransmitter systems in the morphine suppression of jaw-opening reflex in rabbits: the dopaminergic system
Exp. Neurol.
(1979)
S.H.H. Chan et al.
Central neurotransmitter systems in the morphine suppression of jaw-opening reflex in rabbits: the cholinergic system
Exp. Neurol.
(1979)
B. Costall et al.
Serotonergic involvement with neuroleptic catalepsy
Neuropharmacology
(1975)
B. Dahlstrom et al.
A pharmacokinetic approach to morphine analgesia and its relation to regional turnover of rat brain catecholamines
Life Sci.
(1975)
S.G. Dennis et al.
Pain-signalling systems in the dorsal and ventral spinal cord
Pain
(1977)
S.G. Dennis et al.
Pain modulation by 5-hydroxytryptaminergic agents and morphine as measured by three pain tests
Exp. Neurol.
(1980)
S.G. Dennis et al.
Pain modulation by adrenergic agents and morphine as measured by three pain tests
Life Sci.
(1980)
D. Dubuisson et al.
The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brainstem stimulation in rats and cats
Pain
(1977)
K.L. McGilliard et al.
The effect of dopaminergic modifiers on morphine-induced analgesia and respiratory depression
Eur. J. Pharmacol.
(1979)
M.T.C. Price et al.
Ascending catecholamine systems and morphine analgesia
Brain Res.
(1975)

J. Robertson et al.

Evidence for the potentiation of the antinociceptive action of morphine by bromocriptine

Neuropharmacology

(1981)

L.J. Botticelli et al.

Choline-induced attenuation of morphine analgesia in the rat

Commun. Psychopharmacol.

(1977)

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Determining the influence of phasic/escapable (e.g., heat, pressure) and tonic/inescapable (e.g., acetic acid, formalin) types of pain on DA inputs to the BNST may provide further clarification as well (Morgan and Franklin, 1990; Altier and Stewart, 1999; Taylor et al., 2016). Regardless of these distinctions, our conclusion that activating vlPAG/DRDA+ projections to the BNST reduces acute and persistent inflammatory pain provides further evidence that DA signaling can enhance anti-nociception to counteract severe pain (Burrill et al., 1944; Goetzl et al., 1944; Ivy et al., 1944; Dennis and Melzack, 1983; Chudler and Dong, 1995; Altier and Stewart, 1999; Magnusson and Fisher, 2000; Wood et al., 2007; Hagiwara et al., 2013; Megat et al., 2018). Although activation of vlPAG/DRDA+ neurons and their projections to the BNST produced negligible effects on nociceptive sensitivity in female mice, assessment of visceral nociception and valence-specific behaviors revealed an additional role of the projections in sex- and context-dependent locomotion.
Sex differences in pain severity, response, and pathological susceptibility are widely reported, but the neural mechanisms that contribute to these outcomes remain poorly understood. Here we show that dopamine (DA) neurons in the ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DR) differentially regulate pain-related behaviors in male and female mice through projections to the bed nucleus of the stria terminalis (BNST). We find that activation of vlPAG/DR^DA+ neurons or vlPAG/DR^DA+ terminals in the BNST reduces nociceptive sensitivity during naive and inflammatory pain states in male mice, whereas activation of this pathway in female mice leads to increased locomotion in the presence of salient stimuli. We additionally use slice physiology and genetic editing approaches to demonstrate that vlPAG/DR^DA+ projections to the BNST drive sex-specific responses to pain through DA signaling, providing evidence of a novel ascending circuit for pain relief in males and contextual locomotor response in females.
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In contrast, in the hot-plate test, the final response involves not only spinal, but also supraspinal pathways. Dennis and Melzack first described an essential role for the dopamine system in mediating antinociception (Dennis and Melzack, 1983). Basal ganglia, limbic areas, thalamus, periaqueductal gray matter (PAG), and other brain areas modulated by the dopaminergic system play a critical role in the processing of pain (Chudler and Dong, 1995; Hagelberg et al., 2002).
Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson's disease (PD). Pain is a prevalent PD's non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available. Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception. Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1). We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD. Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.
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The association between chronic pain, depression and anxiety has gained particular attention due to high rates of comorbidity. Recent data demonstrated that the mesolimbic reward circuitry is involved in the pathology of chronic pain. Interestingly, the mesolimbic reward circuit participates both in pain perception and in pain relief. The endocannabinoid system (ECS) has emerged as a highly relevant player involved in both pain perception and reward processing. Targeting ECS could become a novel treatment strategy for chronic pain patients. However, little is known about the underlying mechanisms of action of cannabinoids at the intersection of neurochemical changes in reward circuits and chronic pain. Because understanding the benefits and risks of cannabinoids is paramount, the aim of this review is to evaluate the state-of-art knowledge about the involvement of the ECS in dopamine signalling within the reward circuits affected by chronic pain.
Modulation of pain, nociception, and analgesia by the brain reward center
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Evidence from a number of groups also suggests that the mesolimbic dopamine system modulates the perception of nociceptive information, the efficacy of pain medications, and the affective symptoms of chronic pain (Baliki et al., 2010; Cahill et al., 2013; Terzi et al., 2014). Dennis and Melzack (1983) first demonstrated that dopaminergic agents improve symptoms of pain and promote analgesia. On the other hand, malfunction of mesolimbic dopaminergic regions, such as the striatum and the VTA, results in excessive pain (Saadé Atweh et al., 1997).
The midbrain dopamine center comprises a key network for reward, salience, motivation, and mood. Evidence from various clinical and preclinical settings points to the midbrain dopamine circuit as an important modulator of pain perception and pain-induced anxiety and depression. This review summarizes recent findings that shed light to the neuroanatomical, electrophysiological and molecular adaptations that chronic pain conditions promote in the mesolimbic dopamine system. Chronic pain states induce changes in neuronal plasticity and functional connectivity in several parts of the brain reward center, including nucleus accumbens, the ventral tegmental area and the prefrontal cortex. Here, we discuss recent findings on the mechanisms involved in the perception of chronic pain, in pain-induced anxiety and depression, as well as in pain-killer addiction vulnerability. Several new studies also show that the mesolimbic dopamine circuit potently modulates responsiveness to opioids and antidepressants used for the treatment of chronic pain. We discuss recent data supporting a role of the brain reward pathway in treatment efficacy and we summarize novel findings on intracellular adaptations in the brain reward circuit under chronic pain states.
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While chronic pain is considered by some to be a CNS disease, little is understood about underlying neurobiological mechanisms. Addiction models have heuristic value in this regard, because both pain and addictive disorders are characterized by impaired hedonic capacity, compulsive drug seeking, and high stress. In drug addiction such symptomatology has been attributed to reward deficiency, impaired inhibitory control, incentive sensitization, aberrant learning, and anti-reward allostatic neuroadaptations. Here we propose that similar neuroadaptations exist in chronic pain patients.
The antipsychotic aripiprazole induces antinociceptive effects: Possible role of peripheral dopamine D<inf>2</inf> and serotonin 5-HT<inf>1A</inf> receptors
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This is in line with other studies demonstrating that systemic administration of dopaminergic drugs alleviates nociceptive responses in various models. These compounds, however, act as full dopaminergic agonists and are more prone to induce side effects as compared with aripiprazole (Dang et al., 2010; Dennis and Melzack, 1983; Frussa-Filho et al., 1996; Morgan and Franklin 1991; Sarkis et al., 2011; Zarrindast et al., 1999). The doses tested in the present study do not induce any change in motor activity in mice, discarding this potential confound factor (Almeida-Santos et al., 2014).
Aripiprazole is an antipsychotic that acts by multiple mechanisms, including partial agonism at dopamine D₂ and serotonin 5-HT_1A receptors. Since these neurotransmitters also modulate pain and analgesia, we tested the hypothesis that systemic or local administration of aripiprazole induces antinociceptive responses. Systemic aripiprazole (0.1–10 mg/kg; i.p.) injection in mice inhibited formalin-induced paw licking and PGE₂-induced hyperalgesia in the paw pressure test. This effect was mimicked by intra-plantar administration (12.5–100 µg/paw) in the ipsi, but not contralateral, paw. The peripheral action of aripiprazole (100 µg/paw) was reversed by haloperidol (0.1–10 µg/paw), suggesting the activation of dopamine receptors as a possible mechanism. Accordingly, quinpirole (25–100 µg/paw), a full agonist at D₂/D₃ receptors, also reduced nociceptive responses.. In line with the partial agoniztic activity of aripiprazole, low dose of this compound inhibited the effect of quinpirole (both at 25 µg/paw). Finally, peripheral administration of NAN-190 (0.1–10 μg/paw), a 5-HT_1A antagonist, also prevented aripiprazole-induced antinociception. In conclusion, systemic or local administration of aripiprazole induces antinociceptive effects. Similar to its antipsychotic activity, the possible peripheral mechanism involves dopamine D₂ and serotoninergic 5-HT_1A receptors. Aripiprazole and other dopaminergic modulators should be further investigated as new treatments for certain types of pain.

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¹: This research was supported by grant A-7891 to Dr. Melzack from the Natural Sciences and Engineering Research Council of Canada, and by a National Research Service Award to Dr. Dennis from the National Institute of Neurological and Communicative Disorders and Stroke. We are grateful to S. Gutman and F. Boucher for technical assistance. Naloxone hydrochloride was generously provided by Endo Laboratories.

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Effects of cholinergic and dopaminergic agents on pain and morphine analgesia measured by three pain tests

Abstract

Exp. Neurol.

Exp. Neurol.

Neuropharmacology

Life Sci.

Pain

Exp. Neurol.

Life Sci.

Pain

Eur. J. Pharmacol.

Brain Res.

Neuropharmacology

Choline-induced attenuation of morphine analgesia in the rat

Commun. Psychopharmacol.