Analgesic effects of 1′,1′ dimethylheptyl-Δ8-THC-11-oic acid (CT3) in mice

doi:10.1016/S0024-3205(98)00256-2

Life Sciences

Volume 63, Issue 3, 12 June 1998, Pages 161-168

https://doi.org/10.1016/S0024-3205(98)00256-2 Get rights and content

Abstract

The metabolic pathway leading to carboxylic acid derivatives of cannabinoids was discovered more than twenty years ago. While these compounds showed no cannabimimetjc activity, subsequent work documented several biological responses both in vitro and in vivo for the THC acids. These include inhibition of eicosanoid synthesis, antiedema effects, antagonism to PAF actions, inhibition of leucocyte adhesion and anti nociception. In this report we present data further characterizing the analgesic properties of the title substance which is a potent synthetic member of this group. CT3 was effective in the mouse hot plate assay at 48 °C showing an ED-50 of 4.31(3.37–5.83) $mg kg$ when administered i.v (10% Cremophor EL in saline). When given by gavage in peanut oil, it resulted in 30–40% MPE (maximum possible effect) at 10 $mg kg$ with the effect persisting for up to 5 hours. A more potent response was observed in the mouse p-phenylquinone writhing test. When given i.v., it showed an ED-50 of 1.24 (0.84–1.75) $mg kg$ . However, no activity was found with oral administration either in peanut oil or Cremophor EL. At 10 $mg kg$ i.v., a 100% inhibition of the writhing response was seen. The mouse formalin antinociception test was also studied in animals that received CT3 (4.64 $mg kg$ ) I.V. Using three behavioral parameters for activity. The drug showed decreases in each category when compared with vehicle/formalin treated mice. The formalin effect showed a typical two phase, time related, response in which CT3 caused a 64% reduction in the early phase and a 48% reduction in the late phase in a composite score of nociception. Interestingly, it did not alter motor function in the rota rod procedure at 4.64 $mg kg$ i.v.

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However, the selective antagonists of CB2, opioid and TRPV1 receptors had no significant effects on the activities of mouse VD-Hpα in formalin assay, implying that mouse VD-Hpα-induced antinociception is independent of CB2, opioid and TRPV1 receptors. The previous reports have shown that systemic administration of WIN 55,212-2, Δ9-tetrahydrocannabinol, cannabinol, and 1′,1′-dimethylheptyl-Δ8-tetrahydrocannabinol-11-oic acid induced analgesic properties in the acetic acid-induced writhing test (Burstein et al., 1998; Sofia et al., 1975; Vincenzi et al., 2013). In addition, the endocannabinoid system was also involved in the reduction of visceral hyperalgesia.
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It was also reported that, at a dose of 0.1 mg/kg, no response in the ring test for catalepsy was seen suggesting a separation of psychotropic from analgesic activities. In a subsequent study of AJA (CT-3), positive effects were reported in several pain assays.38 These included the mouse hot plate assay at 48 °C, the mouse p-phenylquinone writhing test and the mouse formalin anti-nociception test.
The cannabinoid acids are a structurally heterogeneous group of compounds some of which are endogenous molecules and others that are metabolites of phytocannabinoids. The prototypic endogenous substance is N-arachidonoyl glycine (NAgly) that is closely related in structure to the cannabinoid agonist anandamide. The most studied phytocannabinoid is Δ⁹-THC-11-oic acid, the principal metabolite of Δ⁹-THC. Both types of acids have in common several biological actions such as low affinity for CB1 anti-inflammatory activity and analgesic properties. This suggests that there may be similarities in their mechanism of action, a point that is discussed in this review. Also presented are reports on analogs of the acids that provide opportunities for the development of novel therapeutic agents, such as ajulemic acid.
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IP-751, provided by Indevus Pharmaceuticals (Lexington, Mass), was dissolved in 30% Cremophor for intravenous administration. The doses (1 to 10 mg/kg intravenously) of IP-751 were chosen because, in previous studies, these were the effective doses to suppress somatic pain responses.7–9 Also, IP-751 at doses greater than 10 mg/kg exhibited central effects, affecting motor performance and resulting in catalepsy in rats.10
Ajulemic acid (IP-751) is a synthetic analog of tetrahydrocannabinol, which is a major ingredient of the plant Cannabis. IP-751 reportedly shows potent anti-inflammatory activity and is a powerful analgesic agent. Thus, we examined whether IP-751 can suppress urinary frequency induced by nociceptive stimuli in the bladder.
Continuous cystometry (infusion rate 0.04 mL/min) under urethane anesthesia was performed to evaluate the effect of intravenous injection of IP-751 with or without a cannabinoid-1 receptor antagonist (AM251) or a cannabinoid-2 receptor antagonist (AM630) on bladder function in normal rats and rats with urinary frequency induced by intravesical infusion with 0.25% acetic acid or cyclophosphamide (CYP) (150 mg/kg intraperitoneally, 48 hours before cystometrography).
When 10 mg/kg of IP-751 was injected in normal rats, the intercontraction interval (ICI) and pressure threshold increased. A 0.25% acetic acid infusion induced urinary frequency, as evidenced by a reduction in ICIs, which were suppressed by injection of IP-751 (10 mg/kg). Urinary frequency, indicated by significant ICI reductions, was also observed in the CYP-treated rats. Administration of IP-751 (10 mg/kg) significantly suppressed CYP-induced urinary frequency, as evidenced by the increase in the ICI. When AM251, but not AM630, was administered before IP-751, the IP-751-induced increases in the ICI and pressure threshold were prevented in all three groups. In addition, administration of AM251 alone decreased the ICIs in CYP-treated rats.
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There is increasing evidence that cannabinoid agonists alleviate the abnormal pain sensations associated with animal models of neuropathic and inflammatory pain. However, cannabinoids produce a number of motor and psychotropic side effects. In the present study we found that systemic administration of the cannabinoid acid derivative 1′,1′-dimethylheptyl-Δ-8-tetrahydrocannabinol-11-oic acid (ajulemic acid, IP-751) and the non-selective cannabinoid receptor agonist HU-210 reduced mechanical allodynia in a nerve-injury induced model of neuropathic pain and in the CFA-induced model of inflammatory pain. In contrast, HU-210, but not ajulemic acid reduced motor performance in the rotarod test. These findings suggest that ajulemic acid reduces abnormal pain sensations associated with chronic pain without producing the motor side effects associated with THC and other non-selective cannabinoid receptor agonists.
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In a recent clinical trial CT-3 was shown to be analgesic in a group of patients with neuropathic pain of mixed aetiology, in the absence of marked cannabinoid-like side effects (Karst et al., 2003). Whilst CT-3 appears to be antinociceptive in models of acute pain (Burstein et al., 1998), there are no reports of its activity in animal models of chronic pain, and its mechanism of action is uncertain. The purpose of the present study was to determine the efficacy of CT-3 in models of chronic neuropathic and inflammatory pain in the rat and assess the involvement of the cannabinoid system, as well as to explore the relative contributions of central and peripheral CB receptors.
CT-3 (ajulemic acid) is a synthetic analogue of a metabolite of Δ⁹-tetrahydrocannabinol that has reported analgesic efficacy in neuropathic pain states in man. Here we show that CT-3 binds to human cannabinoid receptors in vitro, with high affinity at hCB1 (K_i 6 nM) and hCB2 (K_i 56 nM) receptors. In a functional GTP-γ-S assay CT-3 was an agonist at both hCB1 and hCB2 receptors (EC₅₀ 11 and 13.4 nM, respectively). In behavioural models of chronic neuropathic and inflammatory pain in the rat, oral administration of CT-3 (0.1–1 mg/kg) produced up to 60% reversal of mechanical hyperalgesia. In both models the antihyperalgesic activity was prevented by the CB1-antagonist SR141716A but not the CB2-antagonist SR144528. In the tetrad of tests for CNS activity, CT-3 (1–10 mg/kg, po) produced dose-related catalepsy, deficits in locomotor performance, hypothermia, and acute analgesia. Comparison of 50% maximal effects in the tetrad and chronic pain assays produced an approximate therapeutic index of 5–10. Pharmacokinetic analysis showed that CT-3 exhibits significant but limited brain penetration, with a brain/plasma ratio of 0.4 measured following oral administration, compared to ratios of 1.0–1.9 measured following subcutaneous administration of WIN55,212-2 or Δ⁹-THC. These data show that CT-3 is a cannabinoid receptor agonist and is efficacious in animal models of chronic pain by activation of the CB1 receptor. Whilst it shows significant cannabinoid-like CNS activity, it exhibits a superior therapeutic index compared to other cannabinoid compounds, which may reflect a relatively reduced CNS penetration.

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Analgesic effects of 1′,1′ dimethylheptyl-Δ8-THC-11-oic acid (CT3) in mice

Abstract

Biochem. Pharmacol.

Life Sci.

Pain

Pain

J. Am. Pharm. Assoc.

The origin and use of cannabis in Eastern Asia

Science

Pharmacodynamics of certain drugs of abuse

Agents and Actions

Analgesic effects of 1′,1′ dimethylheptyl-Δ⁸-THC-11-oic acid (CT3) in mice